Thienopyridine type mevalonolactones

ABSTRACT

The present invention provides a compound of the formula: ##STR1## process for their production, pharmaceutical compositions containing them and their pharmaceutical uses, and intermediates useful for their production and processes for the production of such intermediates.

The present invention relates to novel mevalonolactones having athienopyridine ring, processes for their production, pharmaceuticalcompoistions containing them and their pharmaceutical uses particularlyas hypolipoproteinemic and antiatherosclerotic agents, and intermediatesuseful for their production and processes for the production of suchintermediates.

Some fermentation metabolic products such as compactin, CS-514,Mevinolin or semi-synthetic derivatives or fully synthetic derivativesthereof are known to be inhibitors against HMG-CoA reductase which is arate limiting enzyme for cholesterol biosynthesis. (A. Endo J. MedChem., 28(4) 401 (1985)).

CS-514 and Mevinolin have been clinically proved to be potentiallyuseful anti-hyperlipoproteinemic agents, and they are considered to beeffective for curing or preventing diseases of coronary arteriosclerosisor atherosclerosis. (IXth Int. Symp. Drugs Affect. Lipid Metab., 1986,p30, p31, p66).

However, with respect to fully synthetic derivatives, particularlyhetero aromatic derivatives of inhibitors against HMG-CoA reductase,limited information is disclosed in the following literatures:

WPI ACC No. 84-157675, 86-028274, 86-098816, 86-332070, 87-124519,87-220987, 88-07781, 88-008460, 88-091798, 88-112505, 88-182950,88-234828, 88-258359, 88-265052, 88-280597, 88-300969, 89-15672,89-24911, 89-24913, 89-25270, 89-25474, 89-48221 and 89-78429.

The present inventors have found that mevalonolactone derivatives havinga thienopyridine ring, which has not been known, the correspondingdihydroxy carboxylic acids and salts and esters thereof have highinhibitory activities against cholesterol biosynthesis wherein HMG-CoAreductase acts as a rate limiting enzyme. The present invention has beenaccomplished on the basis of this discovery.

The novel mevalonolactone derivatives of the present invention arerepresented by the following formula I: ##STR2## wherein R¹ and R² areindependently hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, C₁₋₆alkoxy, fluoro, chloro, bromo, ##STR3## (wherein R⁶, R⁷ and R⁸ areindependently hydrogen, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₃₋₇ cycloalkyl,trifluoromethyl, fluoro, chloro or bromo), 2-, 3- or 4-pyridyl, 2- or5-pyrimidyl, 2- or 3-thienyl, 2- or 3-furyl, ##STR4## (wherein R⁶ is asdefined above), --NR⁹ R¹⁰ (wherein R⁹ and R¹⁰ are independentlyhydrogen, C₁₋₄ alkyl, ##STR5## (wherein R⁶ is as defined above, and m is1, 2 or 3), or R⁹ and R¹⁰ together form --(CH₂)_(j) -- (wherein j is 3,4 or 5)); or C₁₋₃ alkyl substituted by ##STR6## (wherein R⁶ is asdefined above) and by 0, 1 or 2 members selected from the groupconsisting of C₁₋₈ alkyl or α- or β-naphthyl; or R¹ and R² together formC₂₋₆ alkylene unsubstituted or substituted by 1 to 3 members selectedfrom the group consisting of C₁₋₄ alkyl, C₃₋₇ cycloalkyl, fluoro, chloroand bromo, and by one member selected from the group consisting of##STR7## (wherein R⁶ is as defined above), or --(CHR²³)_(k)--A--(CHR²⁴)_(l) -- (wherein k and l are respectively 0, 1, 2 or 3, andA is --C(R¹⁸)═C(R¹⁹)-- (wherein R¹⁸ and R¹⁹ are independently hydrogenor C₁₋₃ alkyl), --O--, --S-- or --N(R²⁰)-- (wherein R²⁰ is hydrogen,C₁₋₄ alkyl or ##STR8## (wherein R⁶ is as defined above, and m is 1, 2 or3)), and R²³ and R²⁴ are independently hydrogen or C₁₋₄ alkyl), or--CH═CH--CH═CH--; R³ and R⁴ are independently hydrogen, C₁₋₈ alkyl, C₃₋₇cycloalkyl, C₁₋₃ alkoxy, n-butoxy, i-butoxy sec-butoxy, t-butoxy, R²⁵R²⁶ N-- (wherein R²⁵ and R²⁶ are independently hydrogen or C₁₋₃ alkyl),trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro,bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy,diphenyl-t-butylsilyloxy, hydroxymethyl or --O(CH₂)_(l) OR¹⁵ (whereinR¹⁵ is hydrogen or C₁₋₃ alkyl, and l is 1, 2 or 3); or when located atthe ortho position to each other, R³ and R⁴ may together fOrm--CH═CH--CH═CH-- or methylenedioxy; Y is --CH₂ --, --CH₂ CH₂ --,--CH═CH--, --CH₂ --CH═CH--, --CH═CH--CH₂ --, --C(CH₃)═CH-- or--CH═C(CH₃)--; Z is --Q--CH₂ WCH₂ --CO₂ R¹², ##STR9## (wherein Q is--C(O)--, --C(OR¹³)₂ -- or --CH(OH)--; W is --C(O)--, --C(OR¹³)₂ -- or--C(R¹¹) (OH)--; R¹¹ is hydrogen or C₁₋₃ alkyl; R¹² is hydrogen or R¹⁴(wherein R¹⁴ is alkyl moiety of chemically or physiologicallyhydrolyzable alkyl ester or M (wherein M is NHR²⁷ R²⁸ R²⁹ (wherein R²⁷,R²⁸ and R²⁹ are independently hydrogen or C₁₋₄ alkyl), sodium, potassiumor 1/2 calcium)); two R¹³ are independently primary or secondary C₁₋₆alkyl; or two R¹³ together form --(CH₂)₂ -- or --(CH₂)₃ --); R¹⁶ and R17are independently hydrogen or C₁₋₃ alkyl; or R¹⁶ and R17 together form--CH₂)₂ -- or --(CH₂)₃ --; and R⁵ is hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl,C₃₋₇ cycloalkyl, C₅₋₇ ; cycloalkenyl, or ##STR10## (wherein R⁶ is asdefined above), or C₁₋₃ alkyl substituted by one member selected fromthe group consisting of ##STR11## (wherein R⁶, R⁷ and R⁸ are as definedabove) and by 0, 1 or 2 members selected from the group consisting ofC₁₋₃ alkyl.

Various substituents in the formula I will be described in detail withreference to specific examples. However, it should be understood thatthe present invention is by no means restricted by such specificexamples.

C₁₋₈ alkyl for R¹, R², R³, R⁴ and R⁵ includes, for example, methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl,n-pentyl, 1,2-dimethylpentyl, n-hexyl, n-heptyl and n-octyl.

C₁₋₄ alkyl for R⁶, R⁷, R⁸, R⁹, R¹⁰, R²⁰, R²³, R²⁴, R²⁷, R²⁸ and R²⁹includes, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, sec-butyl and t-butyl.

C₁₋₃ alkyl for R¹¹, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁵ and R²⁶ includes, forexample, methyl, ethyl, n-propyl and i-propyl.

When R¹² is alkyl, R¹⁴ includes methyl, ethyl, n-propyl, i-propyl,c-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl (amyl),i-pentyl and n-hexyl.

C₁₋₆ alkyl for R¹³ includes, for example, methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, sec-butyl, n-pentyl and n-hexyl.

C₃₋₇ cycloalkyl for R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ includes, forexample, cyclopropyl, 1-methylcyclopropyl, 2-methylcyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl and cycloheptyl.

C₁₋₆ alkoxy for R¹ and R² includes, for example, methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, n-pentyloxy andn-hexyloxy.

C₁₋₄ alkoxy for R³ and R⁴ includes, for example, methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy and sec-butoxy.

C₁₋₃ alkoxy for R⁶, R⁷ and R⁸ includes, for example, methoxy, ethoxy,n-propoxy and i-propoxy.

C₂₋₆ alkenyl for R¹, R² and R⁵ includes, for example, vinyl,1-methylvinyl, 1-propenyl, allyl, 1-methyl-1-propenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-butenyl, 1-ethylvinyl,1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl,1-ethyl-2propenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl,2-methyl-1-butenyl, 1-i-propylvinyl and 1-methyl-1-pentenyl.

C₅₋₇ cycloalkenyl for R⁵ includes, for example, 2-cyclopentenyl,2-cyclohexenyl, 2-cycloheptenyl and 4-methyl-2-cyclohexenyl.

M is a metal capable of forming a pharmaceutically acceptable salt andincludes, for example, sodium, potassium and calcium CO₂ M includes, forexample, --CO₂ NH₄ and CO₂ H.(primary to tertiary lower alkylamine), forexample, triethylamine.

Further, these compounds may have at least one or two asymmetric carbonatoms and may have at least two to four optical isomers. The compoundsof the formula I include all of these optical isomers and all of themixtures thereof.

Among compounds having carboxylic acid moieties falling outside thedefinition of --CO₂ R¹² of the carboxylic acid moiety of substitutent Zof the compounds of the present invention, those which undergophysiological hydrolysis, after intake, to produce the correspondingcarboxylic acids (compounds wherein the --CO₂ R¹² moiety is --CO₂ H) areequivalent to the compounds of the present invention.

Now, preferred substitutents of the compounds of the present inventionwill be described.

In the following preferred, more preferred, still further preferred andmost preferred examples, the numerals for the positions of thesubstituents indicate the positions on the thienopyridine ring.

Preferred compound (1) of the formula I is a compound wherein R¹ and R²are independently hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl,fluoro, chloro, bromo, ##STR12## (wherein R⁶, R⁷ and R⁸ areindependently hydrogen, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₃₋₇ cycloalkyl,trifluoromethyl, fluoro, chloro or bromo), 2-, 3- or 4-pyridyl, 2- or3-thienyl, 2- or 3-furyl; C₁₋₃ alkyl, unsubstituted or substituted by 1or 2 members selected from the group consisting of ##STR13## (wherein R⁶is as defined above) and C₁₋₈ alkyl or α- or β-naphthyl; or R¹ and R²together form C₂₋₆ alkylene unsubstituted or substituted by 1 to 3members selected from the group consisting of C₁₋₄ alkyl, C₃₋₇cycloalkyl, fluoro, chloro or bromo and by one member selected from thegroup consisting of ##STR14## (wherein R⁶ is as defined above) or--(CHR²³)_(k) --A--(CHR²⁴)_(l) -- (wherein k and l are independently 0,1, 2 or 3, A is --C(R¹⁸)═c(R¹⁹)-- (wherein R¹⁸ and R¹⁹ are independentlyhydrogen or C₁₋₃ alkyl), --O--, --S-- or 13 N(R²⁰)-- (wherein R²⁰ ishydrogen, C₁₋₄ alkyl or ##STR15## (wherein R⁶ is as defined above and mis 1, 2 or 3)) and R²³ and R²⁴ are independently hydrogen or C₁₋₄ alkyl;R³ and R⁴ are independently hydrogen, C₁₋₈ alkyl, C₁₋₃ alkoxy, n-butoxy,i-butoxy, sec-butoxy, t-butoxy, trifluoromethyl, fluoro, chloro, bromo,phenoxy, benzyloxy, hydroxy, tremethylsilyloxy,diphenyl-t-butylsilyloxy, hydroxymethyl or --O(CH₂)_(l) OR¹⁵ (whereinR¹⁵ is hydrogen or C₁₋₃ alkyl, and l is 1, 2 or 3); when located at theortho position to each other, R³ and R⁴ together form methylenedioxy; Yis --CH₂ CH₂ -- or --CH═CH--; Z is --Q--CH₂ WCH₂ --CO₂ R¹², ##STR16##(wherein Q is --C(O)-- or --CH(OH)--; W is --C(O)-- or --CH(OH)--; andR¹² are as defined above; and R⁵ is C₁₋₈ alkyl, C₂₋₆ alkenyl or C₃₋₇cycloalkyl.

More preferred compound (2) of the formula I is a compound wherein R¹and R² are independently hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇cycloalkyl, ##STR17## (wherein R⁶, R⁷ and R⁸ are independently hydrogen,C₁₋₄ alkyl, C₁₋₃ alkoxy, C₃₋₇ cycloalkyl, trifluoromethyl, fluoro,chloro or bromo) or α- or β-naphthyl; or R¹ and R² together form C₂₋₆alkylene unsubstituted or substituted by 1 to 3 members selected formthe group consisting of C₁₋₄ alkyl, C₃₋₇ cycloalkyl, fluoro, chloro andbromo, and by one member selected from the group consisting of ##STR18##(wherein R⁶ is as defined above); R³ and R⁴ are as defined with respectto the compound (1) and located at 3- and 4-position; Y is --CH₂ CH₂ --or (E)--CH═CH--; Z is as defined with respect to the compound (1); andR⁵ is primary or secondary C₁₋₄ alkyl or C₃₋₆ cycloalkyl.

Still further preferred compound (3) is a compound wherein R¹ and R² areindependently hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl,##STR19## (wherein R⁶, R⁷ and R⁸ are as defined with respect to thecompound (2)); or R¹ and R² together form C₂₋₆ alkylene unsubstituted orsubstituted by 1 to 3 members selected from the group consisting of C₁₋₄alkyl, C₃₋₇ cycloalkyl, fluoro, chloro and bromo, and by one memberselected from the group consisting of ##STR20## (wherein R⁶ is asdefined above); R³ and R⁴ are independently hydrogen, C₁₋₈ alkyl,fluoro, chloro or bromo, and they are located at the 3- and 4-poSition;Y and Z are as defined with respect to the compound (2); and R⁵ isethyl, n-propyl, i-propyl or cyclopropyl.

The most preferred compound (4) is a compound wherein R¹ and R² areindependently hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, sec-butyl, t-butyl, n-pentyl, 1,2-dimethylpentyl, n-hexyl,n-heptyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,4-methylcyclohexyl, cycloheptyl, cyclopropylmethyl, vinyl,1-methylvinyl, 1-propenyl, allyl, 1-methyl-1-propenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-butenyl, 1ethylvinyl,1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl,1-ethyl-2-propenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl,2-methyl-1-butenyl, 1-i-propylvinyl, 1-methyl-1-pentenyl or phenyl; orR¹ and R² together form ethylene, trimethylene, tetramethylene,pentamethylene, methyltetramethylene, chlorotetramethylene,phenyltetramethylene; when R⁴ is hydrogen, R³ is hydrogen, 3-methyl,4-methyl, 3-chloro, 4-chloro, 3-fluoro or 4-fluoro; or R³ and R⁴together form 3-methyl-4-chloro, 3,5-dichloro, 3,5-difluoro,3,5-dimethyl or 3-methyl-4-fluoro; Y and Z are as defined with respectto the compound (2); and R⁵ is i-propyl or cyclopropyl.

Now, particularly preferred specific compounds of the present inventionwill be presented.

(a)(E)-7-[3'-ethyl-4'--(4"-fluorophenyl)-2'-methyl-6'-(1"-methylethyl)thieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position

(b)(E)-7-[4'--(4"-fluorophenyl)-2'-methyl-6'--(1"-methylethyl)thieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position

(c)(E)-7-[4'-(4"-fluorophenyl)-6'-(1"-methylethyl)-2'-phenylthieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position

(d)(E)-7-[4'-(4"-fluorophenyl)-2'-methyl-6'-(1"-methylethyl)-3'-phenylthieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position

(e)(E)-7-[4'-(4'-(4"-fluorophenyl)-2'-isopropyl-6'-(1"-methylethyl)thieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position

(f) (E)-7-[4'-(4"-fluorophenyl)-6'-(1"-methylethyl)-2',3'-tetramethylenethieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position

(g)(E)-7-[6'-cyclopropyl-3'-ethyl-4'-(4"-fluorophenyl)-2'-methylthieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxy-hept-6-enoicacid, a sodium salt, methyl ester, ethyl ether, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position

(h)(E)-7-[4'-(4"-fluorophenyl)-6-(1"-methylethyl)-2',3'-trimethylenethieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position

(i)(E)-7-[6'-cyclopropyl-4'-(4"-fluorophenyl)-2',3'-trimethylenethieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position

(j) (E)-7-[6'-cyclopropyl-4'-(4"-fluorophenyl)-2',3"-pentamethylenethieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position

(k)(E)-7-[6'-cyclopropyl-4'-(4"-fluorophenyl)thieno-[2,3-b]pyridin-5'-yl]3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position.

The mevalonolactones of the formula I can be prepared by the followingreaction scheme. ##STR21##

In the above reaction scheme, R¹, R², R³, R⁴, R⁵ and R¹² are as definedabove with respect to the formula I, and R²¹ and R²² independentlyrepresent C₁₋₄ lower alkyl such as methyl, ethyl, n-propyl, i-propyl orn-butyl.

The compound of the formula VII can be prepared by reacting the compoundof the formula X with the compound of the formula XI, or by oxidizingthe compound of the formula XIV obtained by reacting the compound of theformula XII with the compound of the formula XIII (Japanese UnexaminedPatent Publication No. 10087/1987).

Step A represents a reduction reaction of the ester to a primaryalcohol. Such reduction reaction can be conducted by using various metalhydrides, preferably diisobutylaluminium hydride, in a solvent such astetrahydrofuran, toluene or methylene chloride at a temperature of from-20° to 20° C., preferably from -10° to 10° C.

Step B represents an oxidation reaction of the primary alcohol to analdehyde, which can be conducted by using various oxidizing agents.Preferably, the reaction can be conducted by using pyridiniumchlorochromate in methylene chloride at a temperature of from 0° to 25°C., or by using oxalyl chloride, dimethyl sulfoxide and a tertiary aminesuch as triethylamine (Swern oxidation), or by using a sulfur trioxidepyridine complex.

Step C represents a synthesis of a 3-ethoxy-1-hydroxy-2-propenederivative, which can be prepared by reacting a compound V to a lithiumcompound which has been preliminarily formed by treatingcis-1-ethoxy-2-(tri-n-butylstannyl)ethylene with butyl lithium intetrahydrofuran.

As the reaction temperature, it is preferred to employ a low temperatureat a level of from -60° to -78° C.

Step D represents a synthesis of an enal by acidic hydrolysis. As theacid catalyst, it is preferred to employ p-toluenesulfonic acid,hydrochloric acid or sulfuric acid, and the reaction may be conducted ina solvent mixture of water and tetrahydrofuran or ethanol at atemperature of from 10° to 25° C. The 3-ethoxy-1-hydroxy-2-propenederivative obtained in Step C can be used in Step D without purificationi.e. by simply removing tetra-n-butyl tin formed simultaneously.

Step E represents a double anion addition reaction between the enal IIIand an acetoacetate. Such addition reaction is preferably conducted byusing sodium hydride and n-butyl lithium as the base in tetrahydrofuranat a temperature of from -80° to 0° C., preferably from -30° to -10° C.

Step F represents a reduction reaction of the ketocarboxylate of theformula II, by various reducing agents. This reaction comprisesreduction of carbonyl by e.g. sodium borohydride, sodiumcyanoborohydride, zinc borohydride, disiamylborane, diborane,t-butylaminoborane, pyridine-borane complex, dicyclohexylborane,thexylborane, 9-borabicyclo[3.3.1]nonane, diisopinocamphenyl borane orlithium tri-sec-butyl borohydride to the correspondingdihydroxycarboxylate of the formula I-1.

This reaction can be conducted in a solvent selected from hydrocarbons,halogenated hydrocarbons, C₁₋₄ alcohols, ethers and solvent mixturesthereof, at a temperature of from -100° to 50° C., preferably from -78°to 30° C.

Further, as described in J. Amer. Chem. Soc., 105, 93 (1983), atrialkylborane such as tri-n-butylborane or triethylborane and sodiumborohydride are used at a low temperature. Further, as described inTetrahedron Letters, 28, 155 (1987), the erythro form havingbiologically superior activities can advantageously be obtained by usingan alkoxydialkylborane such as methoxydiethylborane orethoxydiethylborane and sodium borohydride.

This reaction can be conducted by using a solvent mixture of C₁₋₄alcohol and tetrahydrofuran at a temperature of from -80° to -50° C.,preferably from -72° to -68° C. Step G is a step for hydrolyzing theester. The hydrolysis can be conducted by using an equimolar amount of abase, preferably potassium hydroxide or sodium hydroxide, in a solventmixture of water and methanol or ethanol at a temperature of from 10° to25° C. The free acid hereby obtained may be converted to a salt with asuitable base.

Step H is a step for forming a mevalonolactone by the dehydrationreaction of the free hydroxy acid I-2. The dehydration reaction can beconducted in benzene or toluene under reflux while removing theresulting water or by adding a suitable dehydrating agent such asmolecular sieve.

Further, the dehydration reaction may be conducted in dry methylenechloride by using a lactone-forming agent such as carbodiimide,preferably a water soluble carbodiimide such asN-cyclohexyl-N'-[2'-(methylmorpholinium)ethyl]carbodiimide p-toluenesulfonate at a temperature of from 10° to 35° C., preferably from 20° to25° C. Step J represnts a reaction for hydrogenating the double bondconnecting the mevalonolactone moiety and the thienopyridine ring. Thishydrogenation reaction can be conducted by using a catalytic amount ofpalladium-carbon or rhodium-carbon in a solvent such as methanol,ethanol, tetrahydrofuran or acetonitrile at a temperature of from 0° to50° C., preferably from 10° to 25° C.

Step K represents a reaction for the synthesis of an α,β-unsaturatedcarboxylic acid ester, whereby a transform α,β-unsaturated carboxylicacid ester can be obtained by a so-called Horner-Wittig reaction byusing an alkoxycarbonylmethyl phosphonate. The reaction is conducted byusing sodium hydride or potassium t-butoxide as the base in drytetrahydrofuran at a temperature of from -30° to 0° C., preferably from-20° to -15° C.

Step L represents a reduction reaction of the α,β-unsaturated carboxylicacid ester to an allyl alcohol. This reduction reaction can be conductedby using various metal hydrides, preferably diisobutylaluminum hydride,in a solvent such as dry tetrahydrofuran or toluene at a temperature offrom -10° to 10° C., preferably from -10° to 0° C.

Step M represents an oxidation reaction of the allyl alcohol to an enal.This oxidation reaction can be conducted by using various oxidizingagents, particularly activated manganese dioxide, in a solvent such astetrahydrofuran, acetone, ethyl ether or ethyl acetate at a temperatureof from 0° to 100° C., preferably from 15° to 50° C., or in accordancewith Swern oxidation by using oxalyl chloride, dimethylsulfoxide and atertiary amine such as triethylamine.

Step N represents a reaction for the synthesis of an α, β-unsaturatedketone by the selective oxidation of the dihydroxy carboxylic acidester. This reaction can be conducted by using activated manganesedioxide in a solvent such as ethyl ether, tetrahydrofuran, benzene ortoluene at a temperature of from 20° to 80° C., preferably from 40° to80° C.

Further, the compound of the formula I-6 can be prepared from thealdehyde of the formula V by Wadsworth-Emmons coupling reaction (J.Amer. Chem. Soc., 107, 3731 (1985)). It can also be prepared from theenal of the formula II (Tetrahedron Letters, 26, 2951 (1985)).

Further, the compound of the formula I-7 can be prepared by adding adouble anion of an acetoacetate to the aldehyde of the formula XVprepared by the continuous Wittig reaction (WO-8402131) from thealdehyde of the formula V in the same manner as in Step E, to obtain theketocarbaoxylate of the formula XVI, and reducing the carbonyl group inthe same manner as in Step F.

Step AA represents a reduction reaction of the ketocarboxylate of theformula I-6 or XVII by various reducing agents. This reaction comprisesreduction of carbonyl by e.g. sodium borohydride, sodiumcyanoborohydride, zinc borohydride, disiamylborane, diborane,t-butylaminoborane, pyridine-borane complex, dicyclohexylborane,thexylborane, 9-borabicyclo[3.3.1]nonane, diisopinocamphenyl borane orlithium tri-sec-butyl borohydride to the correspondingdihydroxycarboxylate of the formula I-1.

This reaction can be conducted in a solvent selected from hydrocarbons,halogenated hydrocarbons, C₁₋₄ alcohols, ethers and solvent mixturesthereof, at a temperature of from -100° to 50° C., preferably from -78°to 30° C.

Further, as described in J. Amer. Chem. Soc., 105, 593 (1983), atrialkylborane such as tri-n-butylborane or triethylborane and sodiumborohydride are used at a low temperature. Further, as described inTetrahedron Letters, 28, 155 (1987), the erythro form havingbiologically superior activities can advantageously be obtained by usingan alkoxydialkylborane such as methoxydiethylborane orethoxydiethylborane and sodium borohydride.

This reaction can be conducted by using a solvent mixture of C₁₋₄alcohol and tetrahydrofuran at a temperature of from -80° to -50° C.,preferably from -72° to -68° C.

Step BB represents a reaction of reducing the carbonyl group of theketocarboxylate of the formula XVIII or XIX by using various reducingagent to obtain the corresponding dihydroxycarboxylate of the formulaI-7. This reaction can be conducted in the same manner as in Step AA.

Substituents R¹, R², R³, R⁴ and R⁵ in from the compound of the formulaVI which is an intermediate material of the phosphonium compound of theformula XX used in Steps CC-1, DD-1, EE-1 and the like, to the compoundsof the formula XXII, XXIV and XXVI, are those defined with respect tothe formula I excluding substituents having hydroxyl, amino andmonoalkylamino.

Steps CC-1 and CC-2 comprise reacting the compound of the formula XXIwith the compound of the formula XX (wherein Hal is chlorine, bromine oriodine) by Wittig reaction to obtain the compound of the formula XXII,(Step CC-1), followed by hydrolysis of the hydroxyl-protecting group(R³⁰) of the compound XXII in the presence of a catalyst to obtain thecompound of the formual I-1 (Step CC-2).

The phosphonium compound of the formula XX can be obtained byhalogenating the hydroxyl group of the hydroxymethyl at the 5-positionof the thienopyridine ring of the compound of the formula VI by a usualmethod, and then, reacting triphenylphosphine therewith.

The reactions of Steps CC-1 and CC-2 can be conducted in accordance withthe method disclosed in Tetrahedron Letters, 25, 2435 (1984), U.S. Pat.No. 4,650,890, EP 0 244 364A, etc.

Wittig reaction can be conducted in a dry inert solvent. As the inertsolvent, an aliphatic hydrocarbon, toluene or an ether type solvent maybe mentioned. Preferred is the ether type solvent, such as diethylether, 1,2-diethoxyethane, 1,2-dimethoxyethane or tetrahydrofuran.

Wittig reaction can be conducted in a usual manner. A strong base isadded to a solution of the phosphonium compound of the formula XX withina temperature range which does not affect the substituents of thephosphonium compound, to form the corresponding ylide compound, andthen, the aldehyde of the formula XXI is added to the solution to formthe desired compound.

As examples of the strong base, sodium hydride and n-butyl lithium maybe mentioned, and preferred is n-butyl lithium.

The temperature upon the addition of the strong base is from -40° to 25°C., and the temperature upon the addition of the aldehyde is -35° to 30°C.

The hydroxyl-protecting group (R³⁰) of the compound of the formula XXI,XXII, XXIII, XXIV, XXV or XXVI is tri-substituted silyl, preferablydiphenyl-t-butylsilyl, which is usually used as a hydroxyl-protectinggroup. Preferred is a protecting group which can be removed withoutdecomposition of the ester or the lactone. The solvent used for theremoval of the protecting group is an inert solvent such astetrahydrofuran or methanol. The catalyst used for the removal of theprotecting group is one commonly used for the reaction for removal ofsilyl. For example, a mixture of acetic acid and tetrabutylammoniumfluoride in tetrahydrofuran, or hydrochloride in methanol, may bementioned.

The reaction temperature for the removal of the protecting group is from20° to 60° C., preferably from 20° to 30° C.

When there are hydroxyl-protecting groups other than R³⁰ at the time ofthe removal of the protecting group, such protecting groups may beremoved to form hydroxyls.

Steps DD-1 to DD-3 represent Wittig reaction of the compound of theformula XX with the compound of the formula XXIII (Step DD-1), followedby hydrolysis of the acetal to form the hemiacetal, by oxidation of thehemiacetal to form the lactone (Step DD-2), and then, by removal of thehydroxyl-protecting group (R³⁰) (Step DD-3).

The hydroxyl-protecting group (R³⁰) is as defined in Steps CC-1 andCC-2.

The reaction condition for Step DD-1 may be the same as in the method ofStep CC-1.

Step DD-2 represents (1) the hydrolysis and (2) the oxidation. Thehydrolysis can be conducted in a solvent mixture such as 10% HCl intetrahydrofuran or acetic acid/water/tetrahydrofuran, preferably aceticacid/water/tetrahydroruran.

The reaction temperature is from 10° to 100° C., preferably from 20° to60° C.

The oxidation of the hemiacetal formed by the hydrolysis can beconducted under a mild condition. The reaction condition variesdepending upon the type of the oxidizing agent used.

When the oxidizing agent is pyridinium chlorochromate, the reactiontemperature is from 20° to 30° C., and the solvent used is halogenatedhydrocarbons, preferably methylene chloride.

Swern oxidation is conducted by using a mixture system of oxalylchloride/dimethylsulfoxide/triethylamine PG,46 as the oxidizing agent,the reaction temperature is from -60° to -40° C., and the solvent usedis a halogenated hydrocarbon, preferaby methylene chloride.

When the oxidizing agent is N-methylmorpholinoxide anddichloro-tris((phenyl)₃ P)-ruthenium II, the reaction temperature isfrom 0° to 40° C., preferably from 20° to 30° C., and the solvent is drydimethylformamide or acetone.

When the oxidizing agent is AgCO₃ on Celite, the reaction temperature isfrom 0° C. to the boiling point of the reaction solution, preferably atmost 150° C., and the solvent is benzene, toluene, xylene, etc.

The reaction condition for the removal of the protecting group in StepDD-3 may be the same as in the method of Step CC-2.

Steps EE-1 and EE-2 represent Wittig reaction of the compound of theformula XX with the compound of the formula XXV (Step EE-1) followed byremoval of the hydroxyl-protecting group (R³⁰) (Step EE-2).

The hydroxyl-protecting group (R³⁰) is as defined in Steps CC-1 andCC-2.

The reaction condition for the Step EE-1 may be the same as in themethod of Step CC-1.

The reaction condition for removing the protecting group in Step EE-2may be the same as in the method of Step CC-2.

The compounds of the formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8,I-9, II, XVI and XVIII shown in Table I, are typical examples of thecompounds of the present invention.

In Table 1, and in the following description, n- means normal, i- meansiso, sec- means secondary, t- means tertiary and c- means cyclo.Likewise, Me means methyl, Et means ethyl, Pr means propyl, Bu meansbutyl, Pent means pentyl, Hex means hexyl and Ph means phenyl.

                  TABLE 1                                                         ______________________________________                                         ##STR22##                                                                    ______________________________________                                        Compound     YZ                                                               ______________________________________                                        I-1   (R.sup.12 = Et)                                                                           ##STR23##                                                   I-2   (R.sup.12 = H)                                                                           same as above                                                I-3                                                                                             ##STR24##                                                   I-4                                                                                             ##STR25##                                                   I-5   (R.sup.12 = Na)                                                                           ##STR26##                                                   I-6   (R.sup.12 = Et)                                                                           ##STR27##                                                   I-7   (R.sup.12 = Et)                                                                           ##STR28##                                                   I-8   (R.sup.12 = H)                                                                            ##STR29##                                                   I-9   (R.sup.12 = Na)                                                                           ##STR30##                                                   II    (R.sup.12 = Et)                                                                           ##STR31##                                                   XVI   (R.sup.12 = Et)                                                                           ##STR32##                                                   XVIII (R.sup.12 = Et)                                                                           ##STR33##                                                   ______________________________________                                        R.sup.1   R.sup.2     R.sup.3  R.sup.4                                                                              R.sup.5                                 ______________________________________                                        H         H           H        H      i-Pr                                    H         H           4-F      H      i-Pr                                    H         H           4-Cl     H      i-Pr                                    H         H           3-Me     4-F    i-Pr                                    H         H           H        H      c-Pr                                    H         H           4-F      H      c-Pr                                    H         H           4-Cl     H      c-Pr                                    H         H           3-Me     4-F    c-Pr                                    Me        H           H        H      i-Pr                                    Me        H           4-F      H      i-Pr                                    Me        H           4-Cl     H      i-Pr                                    Me        H           3-Me     4-F    i-Pr                                    Me        H           H        H      c-Pr                                    Me        H           4-F      H      c-Pr                                    Me        H           4-Cl     H      c-Pr                                    Me        H           3-Me     4-F    c-Pr                                    Et        H           H        H      i-Pr                                    Et        H           4-F      H      i-Pr                                    Et        H           4-Cl     H      i-Pr                                    Et        H           3-Me     4-F    i-Pr                                    Et        H           H        H      c-Pr                                    Et        H           4-F      H      c-Pr                                    Et        H           4-Cl     H      c-Pr                                    Et        H           3-Me     4-F    c-Pr                                    Et        Me          H        H      i-Pr                                    Et        Me          4-F      H      i-Pr                                    Et        Me          4-Cl     H      i-Pr                                    Et        Me          3-Me     4-F    i-Pr                                    Et        Me          H        H      c-Pr                                    Et        Me          4-F      H      c-Pr                                    Et        Me          4-Cl     H      c-Pr                                    Et        Me          3-Me     4-F    c-Pr                                    n-Pr      H           H        H      i-Pr                                    n-Pr      H           4-F      H      i-Pr                                    n-Pr      H           4-Cl     H      i-Pr                                    n-Pr      H           3-Me     4-F    i-Pr                                    n-Pr      H           H        H      c-Pr                                    n-Pr      H           4-F      H      c-Pr                                    n-Pr      H           4-Cl     H      c-Pr                                    n-Pr      H           3-Me     4-F    c-Pr                                    i-Pr      H           H        H      i-Pr                                    i-Pr      H           4-F      H      i-Pr                                    i-Pr      H           4-Cl     H      i-Pr                                    i-Pr      H           3-Me     4-F    i-Pr                                    i-Pr      H           H        H      c-Pr                                    i-Pr      H           4-F      H      c-Pr                                    i-Pr      H           4-Cl     H      c-Pr                                    i-Pr      H           3-Me     4-F    c-Pr                                    n-Bu      H           H        H      i-Pr                                    n-Bu      H           4-F      H      i-Pr                                    n-Bu      H           4-Cl     H      i-Pr                                    n-Bu      H           3-Me     4-F    i-Pr                                    n-Bu      H           H        H      c-Pr                                    n-Bu      H           4-F      H      c-Pr                                    n-Bu      H           4-Cl     H      c-Pr                                    n-Bu      H           3-Me     4-F    c-Pr                                    i-Bu      H           H        H      i-Pr                                    i-Bu      H           4-F      H      i-Pr                                    i-Bu      H           4-Cl     H      i-Pr                                    i-Bu      H           3-Me     4-F    i-Pr                                    i-Bu      H           H        H      c-Pr                                    i-Bu      H           4-F      H      c-Pr                                    i-Bu      H           4-Cl     H      c-Pr                                    i-Bu      H           3-Me     4-F    c-Pr                                    c-Pent-methyl                                                                           H           H        H      i-Pr                                    c-Pent-methyl                                                                           H           4-F      H      i-Pr                                    c-Pent-methyl                                                                           H           4-Cl     H      i-Pr                                    c-Pent-methyl                                                                           H           3-Me     4-F    i-Pr                                    c-Pent-methyl                                                                           H           H        H      c-Pr                                    c-Pent-methyl                                                                           H           4-F      H      c-Pr                                    c-Pent-methyl                                                                           H           4-Cl     H      c-Pr                                    c-Pent-methyl                                                                           H           3-Me     4-F    c-Pr                                    c-Pr      H           H        H      i-Pr                                    c-Pr      H           4-F      H      i-Pr                                    c-Pr      H           4-Cl     H      i-Pr                                    c-Pr      H           3-Me     4-F    i-Pr                                    c-Pr      H           H        H      c-Pr                                    c-Pr      H           4-F      H      c-Pr                                    c-Pr      H           4-Cl     H      c-Pr                                    c-Pr      H           3-Me     4-F    c-Pr                                    H         Ph          H        H      i-Pr                                    H         Ph          4-F      H      i-Pr                                    H         Ph          4-Cl     H      i-Pr                                    H         Ph          3-Me     4-F    i-Pr                                    H         Ph          H        H      c-Pr                                    H         Ph          4-F      H      c-Pr                                    H         Ph          4-Cl     H      c-Pr                                    H         Ph          3-Me     4-F    c-Pr                                    Ph        Me          H        H      i-Pr                                    Ph        Me          4-F      H      i-Pr                                    Ph        Me          4-Cl     H      i-Pr                                    Ph        Me          3-Me     4-F    i-Pr                                    Ph        Me          H        H      c-Pr                                    Ph        Me          4-F      H      c-Pr                                    Ph        Me          4-Cl     H      c-Pr                                    Ph        Me          3-Me     4-F    c-Pr                                    H         Me          H        H      i-Pr                                    H         Me          4-F      H      i-Pr                                    H         Me          4-Cl     H      i-Pr                                    H         Me          3-Me     4-F    i-Pr                                    H         Me          H        H      c-Pr                                    H         Me          4-F      H      c-Pr                                    H         Me          4-Cl     H      c-Pr                                    H         Me          3-Me     4-F    c-Pr                                    H         i-Pr        H        H      i-Pr                                    H         i-Pr        4-F      H      i-Pr                                    H         i-Pr        4-Cl     H      i-Pr                                    H         i-Pr        3-Me     4-F    i-Pr                                    H         i-Pr        H        H      c-Pr                                    H         i-Pr        4-F      H      c-Pr                                    H         i-Pr        4-Cl     H      c-Pr                                    H         i-Pr        3-Me     4-F    c-Pr                                    H         Et          H        H      i-Pr                                    H         Et          4-F      H      i-Pr                                    H         Et          4-Cl     H      i-Pr                                    H         Et          3-Me     4-F    i-Pr                                    H         Et          H        H      c-Pr                                    H         Et          4-F      H      c-Pr                                    H         Et          4-Cl     H      c-Pr                                    H         Et          3-Me     4-F    c-Pr                                    H         n-Pr        H        H      i-Pr                                    H         n-Pr        4-F      H      i-Pr                                    H         n-Pr        4-Cl     H      i-Pr                                    H         n-Pr        3-Me     4-F    i-Pr                                    H         n-Pr        H        H      c-Pr                                    H         n-Pr        4-F      H      c-Pr                                    H         n-Pr        4-Cl     H      c-Pr                                    H         n-Pr        3-Me     4-F    c-Pr                                    H         n-Bu        H        H      i-Pr                                    H         n-Bu        4-F      H      i-Pr                                    H         n-Bu        4-Cl     H      i-Pr                                    H         n-Bu        3-Me     4-F    i-Pr                                    H         n-Bu        H        H      c-Pr                                    H         n-Bu        4-F      H      c-Pr                                    H         n-Bu        4-Cl     H      c-Pr                                    H         n-Bu        3-Me     4-F    c-Pr                                    Me        Me          H        H      i-Pr                                    Me        Me          4-F      H      i-Pr                                    Me        Me          4-Cl     H      i-Pr                                    Me        Me          3-Me     4-F    i-Pr                                    Me        Me          H        H      c-Pr                                    Me        Me          4-F      H      c-Pr                                    Me        Me          4-Cl     H      c-Pr                                    Me        Me          3-Me     4-F    c-Pr                                    c-Pent-methyl                                                                           Me          H        H      i-Pr                                    c-Pent-methyl                                                                           Me          4-F      H      i-Pr                                    c-Pent-methyl                                                                           Me          4-Cl     H      i-Pr                                    c-Pent-methyl                                                                           Me          3-Me     4-F    i-Pr                                    c-Pent-methyl                                                                           Me          H        H      c-Pr                                    c-Pent-methyl                                                                           Me          4-F      H      c-Pr                                    c-Pent-methyl                                                                           Me          4-Cl     H      c-Pr                                    c-Pent-methyl                                                                           Me          3-Me     4-F    c-Pr                                    n-Pr      Et          H        H      i-Pr                                    n-Pr      Et          4-F      H      i-Pr                                    n-Pr      Et          4-Cl     H      i-Pr                                    n-Pr      Et          3-Me     4-F    i-Pr                                    n-Pr      Et          H        H      c-Pr                                    n-Pr      Et          4-F      H      c-Pr                                    n-Pr      Et          4-Cl     H      c-Pr                                    n-Pr      Et          3-Me     4-F    c-Pr                                    n-Bu      n-Pr        H        H      i-Pr                                    n-Bu      n-Pr        4-F      H      i-Pr                                    n-Bu      n-Pr        4-Cl     H      i-Pr                                    n-Bu      n-Pr        3-Me     4-F    i-Pr                                    n-Bu      n-Pr        H        H      c-Pr                                    n-Bu      n-Pr        4-F      H      c-Pr                                    n-Bu      n-Pr        4-Cl     H      c-Pr                                    n-Bu      n-Pr        3-Me     4-F    c-Pr                                    Cl        Me          H        H      i-Pr                                    Cl        Me          4-F      H      i-Pr                                    Cl        Me          4-Cl     H      i-Pr                                    Cl        Me          3-Me     4-F    i-Pr                                    Cl        Me          H        H      c-Pr                                    Cl        Me          4-F      H      c-Pr                                    Cl        Me          4-Cl     H      c-Pr                                    Cl        Me          3-Me     4-F    c-Pr                                    Cl        i-Pr        H        H      i-Pr                                    Cl        i-Pr        4-F      H      i-Pr                                    Cl        i-Pr        4-Cl     H      i-Pr                                    Cl        i-Pr        3-Me     4-F    i-Pr                                    Cl        i-Pr        H        H      c-Pr                                    Cl        i-Pr        4-F      H      c-Pr                                    Cl        i-Pr        4-Cl     H      c-Pr                                    Cl        i-Pr        3-Me     4-F    c-Pr                                    MeO       Me          H        H      i-Pr                                    MeO       Me          4-F      H      i-Pr                                    MeO       Me          4-Cl     H      i-Pr                                    MeO       Me          3-Me     4-F    i-Pr                                    MeO       Me          H        H      c-Pr                                    MeO       Me          4-F      H      c-Pr                                    MeO       Me          4-Cl     H      c-Pr                                    MeO       Me          3-Me     4-F    c-Pr                                    MeO       i-Pr        H        H      i-Pr                                    MeO       i-Pr        4-F      H      i-Pr                                    MeO       i-Pr        4-Cl     H      i-Pr                                    MeO       i-Pr        3-Me     4-F    i-Pr                                    MeO       i-Pr        H        H      c-Pr                                    MeO       i-Pr        4-F      H      c-Pr                                    MeO       i-Pr        4-Cl     H      c-Pr                                    MeO       i-Pr        3-Me     4-F    c-Pr                                    Me.sub.2 N                                                                              Me          H        H      i-Pr                                    Me.sub.2 N                                                                              Me          4-F      H      i-Pr                                    Me.sub.2 N                                                                              Me          4-Cl     H      i-Pr                                    Me.sub.2 N                                                                              Me          3-Me     4-F    i-Pr                                    Me.sub.2 N                                                                              Me          H        H      c-Pr                                    Me.sub.2 N                                                                              Me          4-F      H      c-Pr                                    Me.sub.2 N                                                                              Me          4-Cl     H      c-Pr                                    Me.sub.2 N                                                                              Me          3-Me     4-F    c-Pr                                    Cl        Cl          H        H      i-Pr                                    Cl        Cl          4-F      H      i-Pr                                    Cl        Cl          4-Cl     H      i-Pr                                    Cl        Cl          3-Me     4-F    i-Pr                                    Cl        Cl          H        H      c-Pr                                    Cl        Cl          4-F      H      c-Pr                                    Cl        Cl          4-Cl     H      c-Pr                                    Cl        Cl          3-Me     4-F    c-Pr                                    H         Br          H        H      i-Pr                                    H         Br          4-F      H      i-Pr                                    H         Br          4-Cl     H      i-Pr                                    H         Br          3-Me     4-F    i-Pr                                    H         Br          H        H      c-Pr                                    H         Br          4-F      H      c-Pr                                    H         Br          4-Cl     H      c-Pr                                    H         Br          3-Me     4-F    c-Pr                                    H         Hex         H        H      i-Pr                                    H         Hex         4-F      H      i-Pr                                    H         Hex         4-Cl     H      i-Pr                                    H         Hex         3-Me     4-F    i-Pr                                    H         Hex         H        H      c-Pr                                    H         Hex         4-F      H      c-Pr                                    H         Hex         4-Cl     H      c-Pr                                    H         Hex         3-Me     4-F    c-Pr                                    H         CHCH.sub.2  H        H      i-Pr                                    H         CHCH.sub.2  4-F      H      i-Pr                                    H         CHCH.sub.2  4-Cl     H      i-Pr                                    H         CHCH.sub.2  3-Me     4-F    i-Pr                                    H         CHCH.sub.2  H        H      c-Pr                                    H         CHCH.sub.2  4-F      H      c-Pr                                    H         CHCH.sub.2  4-Cl     H      c-Pr                                    H          CHCH.sub.2 3-Me     4-F    c-Pr                                    PhCH.sub.2                                                                              Ph          H        H      i-Pr                                    PhCH.sub.2                                                                              Ph          4-F      H      i-Pr                                    PhCH.sub.2                                                                              Ph          4-Cl     H      i-Pr                                    PhCH.sub.2                                                                              Ph          3-Me     4-F    i-Pr                                    PhCH.sub.2                                                                              Ph          H        H      c-Pr                                    PhCH.sub.2                                                                              Ph          4-F      H      c-Pr                                    PhCH.sub.2                                                                              Ph          4-Cl     H      c-Pr                                    PhCH.sub.2                                                                              Ph          3-Me     4-F    c-Pr                                    2-naphthyl                                                                              Me          H        H      i-Pr                                    2-naphthyl                                                                              Me          4-F      H      i-Pr                                    2-naphthyl                                                                              Me          4-Cl     H      i-Pr                                    2-naphthyl                                                                              Me          3-Me     4-F    i-Pr                                    2-naphthyl                                                                              Me          H        H      c-Pr                                    2-naphthyl                                                                              Me          4-F      H      c-Pr                                    2-naphthyl                                                                              Me          4-Cl     H      c-Pr                                    2-naphthyl                                                                              Me          3-Me     4-F    c-Pr                                    3-Pyridyl Me          H        H      i-Pr                                    3-Pyridyl Me          4-F      H      i-Pr                                    3-Pyridyl Me          4-Cl     H      i-Pr                                    3-Pyridyl Me          3-Me     4-F    i-Pr                                    3-Pyridyl Me          H        H      c-Pr                                    3-Pyridyl Me          4-F      H      c-Pr                                    3-Pyridyl Me          4-Cl     H      c-Pr                                    3-Pyridyl Me          3-Me     4-F    c-Pr                                    H         H           H        H      H                                       H         H           4-F      H      H                                       H         H           4-Cl     H      H                                       H         H           3-Me     4-F    H                                       H         H           H        H      Me                                      H         H           4-F      H      Me                                      H         H           4-Cl     H      Me                                      H         H           3-Me     4-F    Me                                      H         H           H        H      Et                                      ______________________________________                                        R.sup.1                                                                             R.sup.2 R.sup.3      R.sup.4                                                                              R.sup.5                                     ______________________________________                                        H     H       4-F          H      Et                                          H     H       4-Cl         H      Et                                          H     H       3-Me         4-F    Et                                          H     H       H            H      n-Pr                                        H     H       4-F          H      n-Pr                                        H     H       4-Cl         H      n-Pr                                        H     H       3-Me         4-F    n-Pr                                        H     H       H            H      n-Hex                                       H     H       4-F          H      n-Hex                                       H     H       4-Cl         H      n-Hex                                       H     H       3-Me         4-F    n-Hex                                       H     H       H            H      C(CH.sub.3)CH.sub.2                         H     H       4-F          H      C(CH.sub.3)CH.sub.2                         H     H       4-Cl         H      C(CH.sub.3)CH.sub.2                         H     H       3-Me         4-F    C(CH.sub.3)CH.sub.2                         H     H       H            H      c-Hex                                       H     H       4-F          H      c-Hex                                       H     H       4-Cl         H      c-Hex                                       H     H       3-Me         4-F    c-Hex                                       H     H       H            H      Cyclo-3-pentenyl                            H     H       4-F          H      Cyclo-3-pentenyl                            H     H       4-Cl         H      Cyclo-3-pentenyl                            H     H       3-Me         4-F    Cyclo-3-pentenyl                            H     H       H            H      Ph                                          H     H       4-F          H      Ph                                          H     H       4-Cl         H      Ph                                          H     H       3-Me         4-F    Ph                                          H     H       H            H      CH.sub.2 Ph                                 H     H       4-F          H      CH.sub.2 Ph                                 H     H       4-Cl         H      CH.sub.2 Ph                                 H     H       3-Me         4-F    CH.sub.2 Ph                                 H     H       4-c-Pr       H      i-Pr                                        H     H       4-c-Pr       H      c-Pr                                        H     H       4-MeO        H      i-Pr                                        H     H       4-MeO        H      c-Pr                                        H     H       4-N(Me).sub.2                                                                              H      c-Pr                                        H     H       4-CF.sub.3   H      c-Pr                                        H     H       4-Ph         H      c-Pr                                        H     H       4-OH         H      c-Pr                                        H     H       4-OCH.sub.2 Ph                                                                             H      c-Pr                                        H     H       4-OSiMe.sub.3                                                                              H      c-Pr                                        H     H       4-CH.sub.2 OH                                                                              H      c-Pr                                        H     H       4-OCH.sub.2 CH.sub.2 OMe                                                                   H      c-Pr                                        H     H       3,4-OCH.sub.2 O   c-Pr                                          H     H       3,4-CHCHCHCH      c-Pr                                          ______________________________________                                        R.sup.1R.sup.2    R.sup.3  R.sup.4  R.sup.5                                   ______________________________________                                        (CH.sub.2).sub.2 CH(Me)CH.sub.2                                                                 H        H        i-Pr                                      (CH.sub.2).sub.2 CH(Me)CH.sub.2                                                                 4-F      H        i-Pr                                      (CH.sub.2).sub.2 CH(Me)CH.sub.2                                                                 4-Cl     H        i-Pr                                      (CH.sub.2).sub.2 CH(Me)CH.sub.2                                                                 3-Me     4-F      i-Pr                                      (CH.sub.2).sub.2 CH(Me)CH.sub.2                                                                 H        H        c-Pr                                      (CH.sub.2).sub.2 CH(Me)CH.sub.2                                                                 4-F      H        c-Pr                                      (CH.sub.2).sub.2 CH(Me)CH.sub.2                                                                 4-Cl     H        c-Pr                                      (CH.sub.2).sub.2 CH(Me)CH.sub.2                                                                 3-Me     4-F      c-Pr                                      (CH.sub.2).sub.2 OCH.sub.2                                                                      H        H        i-Pr                                      (CH.sub.2).sub.2 OCH.sub.2                                                                      4-F      H        i-Pr                                      (CH.sub.2).sub.2 OCH.sub.2                                                                      4-Cl     H        i-Pr                                      (CH.sub.2).sub.2 OCH.sub.2                                                                      3-Me     4-F      i-Pr                                      (CH.sub.2).sub.2 OCH.sub.2                                                                      H        H        c-Pr                                      (CH.sub.2).sub.2 OCH.sub.2                                                                      4-F      H        c-Pr                                      (CH.sub.2).sub.2 OCH.sub.2                                                                      4-Cl     H        c-Pr                                      (CH.sub.2).sub.2 OCH.sub.2                                                                      3-Me     4-F      c-Pr                                      (CH.sub.2).sub.2 N(Me)CH.sub.2                                                                  H        H        i-Pr                                      (CH.sub.2).sub.2 N(Me)CH.sub.2                                                                  4-F      H        i-Pr                                      (CH.sub.2).sub.2 N(Me)CH.sub.2                                                                  4-Cl     H        i-Pr                                      (CH.sub.2).sub.2 N(Me)CH.sub.2                                                                  3-Me     4-F      i-Pr                                      (CH.sub.2).sub.2 N(Me)CH.sub.2                                                                  H        H        c-Pr                                      (CH.sub.2).sub.2 N(Me)CH.sub.2                                                                  4-F      H        c-Pr                                      (CH.sub.2).sub.2 N(Me)CH.sub.2                                                                  4-Cl     H        c-Pr                                      (CH.sub.2).sub.2 N(Me)CH.sub.2                                                                  3-Me     4-F      c-Pr                                      (CH.sub.2).sub.2 SCH.sub.2                                                                      H        H        i-Pr                                      (CH.sub.2).sub.2 SCH.sub.2                                                                      4-F      H        i-Pr                                      (CH.sub.2).sub.2 SCH.sub.2                                                                      4-Cl     H        i-Pr                                      (CH.sub.2).sub.2 SCH.sub.2                                                                      3-Me     4-F      i-Pr                                      (CH.sub.2).sub.2 SCH.sub.2                                                                      H        H        c-Pr                                      (CH.sub.2).sub.2 SCH.sub.2                                                                      4-F      H        c-Pr                                      (CH.sub.2).sub.2 SCH.sub.2                                                                      4-Cl     H        c-Pr                                      (CH.sub.2).sub.2 SCH.sub.2                                                                      3-Me     4-F      c-Pr                                      CHCHCHCH          H        H        i-Pr                                      CHCHCHCH          4-F      H        i-Pr                                      CHCHCHCH          4-Cl     H        i-Pr                                      CHCHCHCH          3-Me     4-F      i-Pr                                      CHCHCHCH          H        H        c-Pr                                      CHCHCHCH          4-F      H        c-Pr                                      CHCHCHCH          4-Cl     H        c-Pr                                      CHCHCHCH          3-Me     4-F      c-Pr                                      (CH.sub.2).sub.4  H        H        i-Pr                                      (CH.sub.2).sub.4  4-F      H        i-Pr                                      (CH.sub.2).sub.4  4-Cl     H        i-Pr                                      (CH.sub.2).sub.4  3-Me     4-F      i-Pr                                      (CH.sub.2).sub.4  H        H        c-Pr                                      (CH.sub.2).sub.4  4-F      H        c-Pr                                      (CH.sub.2).sub.4  4-Cl     H        c-Pr                                      (CH.sub.2).sub.4  3-Me     4-F      c-Pr                                      (CH.sub.2).sub.3  H        H        i-Pr                                      (CH.sub.2).sub.3  4-F      H        i-Pr                                      (CH.sub.2).sub.3  4-Cl     H        i-Pr                                      (CH.sub.2).sub.3  3-Me     4-F      i-Pr                                      (CH.sub.2).sub.3  H        H        c-Pr                                      (CH.sub.2).sub.3  4-F      H        c-Pr                                      (CH.sub.2).sub.3  4-Cl     H        c-Pr                                      (CH.sub.2).sub.3  3-Me     4-F      c-Pr                                      (CH.sub.2).sub.5  H        H        i-Pr                                      (CH.sub.2).sub.5  4-F      H        i-Pr                                      (CH.sub.2).sub.5  4-Cl     H        i-Pr                                      (CH.sub.2).sub.5  3-Me     4-F      i-Pr                                      (CH.sub.2).sub.5  H        H        c-Pr                                      (CH.sub.2).sub.5  4-F      H        c-Pr                                      (CH.sub.2).sub.5  4-Cl     H        c-Pr                                      (CH.sub.2).sub.5  3-Me     4-F      c-Pr                                      (CH.sub.2).sub. 2 CH(Cl)CH.sub.2                                                                H        H        i-Pr                                      (CH.sub.2).sub.2 CH(Cl)CH.sub.2                                                                 4-F      H        i-Pr                                      (CH.sub.2).sub.2 CH(Cl)CH.sub.2                                                                 4-Cl     H        i-Pr                                      (CH.sub.2).sub.2 CH(Cl)CH.sub.2                                                                 3-Me     4-F      i-Pr                                      (CH.sub.2).sub.2 CH(Ph)CH.sub.2                                                                 H        H        i-Pr                                      (CH.sub.2).sub.2 CH(Ph)CH.sub.2                                                                 4-F      H        i-Pr                                      (CH.sub.2).sub.2 CH(Ph)CH.sub.2                                                                 4-Cl     H        i-Pr                                      (CH.sub.2).sub.2 CH(Ph)CH.sub.2                                                                 3-Me     4-F      i-Pr                                      ______________________________________                                    

Further, pharmaceutically acceptable salts such as potassium salts, 1/2calcium salts, esters such as methyl ester, n-propyl ester, i-propylester, c-propyl ester, n-butyl ester, i-butyl ester, sec-butyl ester,t-butyl ester, n-pentyl ester, i-pentyl ester and n-hexyl ester, orammonium salts or trimethylamine salts of these compounds can beprepared in the same manner.

The compounds of the present invention exhibit high inhibitoryactivities against the cholesterol biosynthesis wherein HMG-CoAreductase acts as a rate limiting enzyme, as shown by the test resultsgiven hereinafter, and thus are capable of suppressing or ruducing theamount of cholesterol in blood as lipoprotein. Thus, the compounds ofthe present invention are useful as curing agents againsthyperlipidemia, hyperlipoproteinemia and atheroscleosis.

They may be formulated into various suitable formulations depending uponthe manner of the administration. The compounds of the present inventionmay be administered in the form of free acids or in the form ofphysiologically hydrolyzable and acceptable esters or lactones, orpharmaceutically acceptable salts.

The pharmaceutical composition of the present invention is preferablyadministered orally in the form of the compound of the present inventionby itself or in the form of powders, granules, tablets or capsulesformulated by mixing the compound of the present invention with asuitable pharmaceutically acceptable carrier including a binder such ashydroxypropyl cellulose, syrup, gum arabic, gelatin, sorbitol,tragacanth gum, polyvinyl pyrrolidone or CMC-Ca, an excipient such aslactose, sugar, corn starch, calcium phosphate, sorbitol, glycine orcrystal cellulose powder, a lubricant such as magnesium stearate, talc,polyethylene glycol or silica, and a disintegrator such as potatostarch.

However, the pharmaceutical composition of the present invention is notlimited to such oral administration and it is applicable for parenteraladministration. For example, it may be administered in the form of e.g.a suppository formulated by using oily base material such as cacaobutter, polyethylene glycol, lanolin or fatty acid triglyceride, atransdermal therapeutic base formulated by using liquid paraffin, whitevaseline, a higher alcohol, Macrogol ointment, hydrophilic ointment orhydro-gel base material, an injection formulation formulated by usingone or more materials selected from the group consisting of polyethyleneglycol, hydro-gel base material, distilled water, distilled water forinjection and an excipient such as lactose or corn starch, or aformulation for administration through mucous memberanes such as anocular mucous membrane, a nasal mucous membrane and an oral mucousmembrane.

Further, the compounds of the present invention may be combined withbasic ion-exchange resins which are capable of binding bile acids andyet not being absorbed by the gastrointestinal tract.

The daily dose of the compound is from 0.05 to 500 mg, preferably from0.5 to 50 mg, for an adult. It is administered from once to three timesper day. The dose may of course be varied depending upon the age, theweight or the condition of illness of the patient.

The compounds of the formulas II to IX are novel, and they are importantintermediates for the preparation of the compounds of the formula I.Accordingly, the present invention relates also to the compounds of theformulas II to IX and the processes for their production.

Now, the present invention will be described in further detail withreference to Test Examples for the pharmacological activities of thecompounds of the present invention, their Preparation Examples andformulation Examples. However, it should be understood that the presentinvention is by no menas restricted by such specific Examples.

PHARMACOLOGICAL TEST EXAMPLES Test A: Inhibition of cholesterolbiosynthesis from acetate in vitro

Enzyme solution was prepared from liver of male Wistar rat billialyconnulated and discharged bile for over 24 hours. Liver was cut out atmid-dark and microsome and supernatant fraction which was precipitablewith 40-80% of solution of ammonium sulfate (sup fraction) were preparedfrom liver homogenate according to the modified method of Knauss et.al.; Kuroda, M., et. al., Biochim. Biophys. Acta, 489, 119 (1977). Forassay of cholesterol biosynthesis, microsome (0.1 mg protein) and supfraction (1.0 mg protein) were incubated for 2 hours at 37° C. in 200 μlof the reaction mixture containing ATP; 1 mM, Glutathione; 6 mM,Glucose-1-phosphate; 10 mM, AND; 0.25 mM, NADP; 0.25 mM, CoA; 0.04 mMand 0.2 mM [2-¹⁴ C]sodium acetate (0.2 μCi) with 4 μl of test compoundsolution dissolved in water or dimethyl sulfoxide. To stop reaction andsaponify, 1 ml of 15% EtOH-KOH was added to the reactions and heated at75° C. for 1 hour. Nonsaponifiable lipids were extracted with petroleumether and incorporated ¹⁴ C radioactivity was counted. Inhibitoryactivity of compounds was indicated with IC50.

Test B: Inhibition of cholesterol biosynthesis in culture cells

Hep G2 cells at over 5th passage were seeded to 12 well plates andincubated with Dulbecco's modified Eagle (DME) medium containing 10% offetal bovine serum (FBS) at 37° C., 5% CO₂ until cells -were confluentfor about 7 days. Cells were exposed to the DME medium containing 5% oflipoprotein deficient serum (LpDS) prepared by ultracentrifugationmethod for over 24 hours. Medium was changed to 0.5 ml of fresh 5% LpDScontaining DME before assay and 10 μl of test compound solutiondissolved in water or DMSO were added. 0.2 μCi of [2-¹⁴ C]sodium acetate(20 μl) was added at 0 hr(B 1) or 4 hrs(B 2) after addition ofcompounds. After 4 hrs further incubation with [2-¹⁴ C]sodium acetate,medium was removed and cells were washed with phosphate buffered saline(PBS) chilled at 4° C. Cells were scraped with rubber policeman andcollected to tubes with PBS and digested with 0.2 ml of 0.5N KOH at 37°C. Aliquot of digestion was used for protein analysis and remaining wassaponified with 1 ml of 15% EtOH-KOH at 75° C. for 1 hour.Nonsaponifiable lipids were extracted with petroleum ether and ¹⁴ Cradioactivity was counted. Counts were revised by cell protein andindicated with DPM/mg protein. Inhibitory activity of compounds wasindicated with IC50.

Test C: Inhibition of cholesterol biosynthesis in vivo

Male Sprague-Dawley rats weighing about 150 g were fed normal Purinachow diet and water ad libitum, and exposed to 12 hours light/12 hoursdark lighting pattern (2:00 PM-2:00 AM dark) prior to use for in vivoinhibition test of cholesterol biosynthesis. Animals were separatedgroups consisting of five rats as to be average mean body weight in eachgroups. Test compounds at dosage of 0.02-0.2 mg/kg body weight (0.4ml/100 g body weight), were dissolved in water or suspended in 0 5%methyl cellulose and orally administered at 2-3 hours before mid-dark(8:00 PM), while cholesterol biosynthesis reaches to maximum in rats. Ascontrol, rats were orally administered only water or vehicle. At 90minutes after sample administration, rats were injectedintraperitoneally with 10 μCi of [2-¹⁴ C]sodium acetate at volume of 0.2ml per one. 2 Hours later, blood samples were obtained and serum wereseparated immediately. Total lipids were extracted according to themethod of Folch et al. and saponified with EtOH-KOH. Nonsaponifiablelipids were extracted with petroleum ether and radio activityincorporated into nonsaponifiable lipids was counted.

Inhibitory activity was indicated as percent decrease of counts intesting groups (DPM/2 ml serum/2 hours) from that in control group.

With respect to the compounds of the present invention, the inhibitoryactivities against the cholesterol biosynthesis in which HMG-CoAreductase serves as a rate limiting enzyme, were measured by the aboveTest A and B. The results are shown in Tables 2, 3-1 and 3-2.

The chemical structure of Reference Compound is shown as follows.##STR34##

IC₅₀ of CS-514 in Test A was 9.0×10⁻⁹ M/l.

The relative activities of the compounds of the present invention basedon the activities of CS-514 by Test A being evaluated to be 1, are shownin Table 2.

                  TABLE 2-2:                                                      ______________________________________                                        Relative activities by Test A                                                 Compound of                                                                   the present invention                                                                          Relative activities                                          ______________________________________                                        I-5-1            0.55                                                         I-1-1            0.50                                                         I-5-2            0.51                                                         I-5-5            0.31                                                         I-5-6            4.1                                                          I-5-7            0.36                                                         I-5-8            0.32                                                         I-5-9            2.9                                                           I-5-10          0.21                                                         ______________________________________                                    

IC₅₀ of CS-514 in Test B-1 was 1.37×10⁻⁶ M/l.

The relative activities of the compound of the present invention basedon the activities of CS-514 by Test B-1 being evaluated to be 1, areshown in Table 3-1.

                  TABLE 3-1:                                                      ______________________________________                                        Relative activities by Test B-1                                               Compound of                                                                   the present invention                                                                          Relative activities                                          ______________________________________                                        I-5-1            152                                                          I-1-1            196                                                          I-5-2            76                                                           II-2             152                                                          I-5-4            1.4                                                          I-5-5            62                                                           I-5-6            152                                                           I-5-11          60                                                           ______________________________________                                    

Further, the Test B-1, the inhibitory activities of the compound of thepresent invention at a concentration of 1.0×10⁻⁶ mol/l are shown inTable 3-2.

                  TABLE 3-2:                                                      ______________________________________                                        Inhibitory activities of the compound of                                      the present invention at a concentration of                                   1.0 × 10.sup.-.sup.6  mol/l by Test B-1                                 Compound of                                                                   the present invention                                                                          Relative activities                                          ______________________________________                                        I-5-3            46.8                                                         I-5-4            48.2                                                         I-5-5            69.8                                                         I-5-7            64.1                                                         I-5-8            63.6                                                         I-5-9            62.4                                                          I-5-10          53.6                                                         ______________________________________                                    

Results of the measurement of the inhibitory activities by Test C

The percent decreases of counts after the oral administration of 0.2mg/kg of compound I-5-11 and I-3-11 were 65% and 68%, respectively,relative to the measured value of the control group. The percentdecrease of counts after the oral administration of 0.2 mg/kg of CS-514was 34% under the same condition. As is evident from the foregoing, thecompounds of the present ivention exhibited activities equivalent orsuperior to the reference compound CS-514 in Tests A, B-1 and C.

Test D: Acute toxicity

A 0.5% CMC suspension of a test compound was orally administered to ICRmale mice (group of three mice). The acute toxicity was determined basedon the mortality after seven darys. With compound I-5-1, I-5-2, I-5-8,I-5-9 and I-5-10 of the present ivnention, the mortality was 0% evenwhen they were orally administered in an amount of 1,000 mg/kg,respectively.

EXAMPLE 1 Ethyl(E)-7-[3'-ethyl-4'-(4"-fluorophenyl)-2'-methyl-6'-(1"-methylethyl)thieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoate(Compound I-1-1)

This compound was prepared by the synthesis comprising the followingreaction steps Example 1-a₀ to Example 1-b.

EXAMPLE 1-a₀ Ethyl3-ethyl-4-(4'-fluorophenyl)-2-methyl-6-(1'-methylethyl)thieno[2,3-b]pyridin-5-ylcarboxylate(Compound VII-1)

(This compound was prepared in accordance with the method disclosed inJ. Heterocycl. Chem., 4, 565, (1967).)

15.1 g (57.3 mmol) of2-amino-4-ethyl-3-(4'-fluoro-benzoyl)-5-methylthiophene (prepared by themethod disclosed in J. Med. Chem., 17, 624 (1974)), 9.07 g (57.3 mmol)of ethylisobutylyl acetate and 0.6 ml of concentrated sulfuric acid,were dissolved in 60 ml of glacial acetic acid, and the solution washeated at 120° C. for 5 hours.

The reaction mixture was cooled to room temperature and gradually addedto a cold mixture of 90 ml of concentrated aqueous ammonia and 300 ml ofwater.

The oily substance thereby freed was extracted with ethyl acetate,washed with water and with a saturated sodium chloride aqueous solutionand dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure, and the residue was subjected to silica gelcolumn chromatography (eluent: hexane/ethyl acetate=10/1) to obtain thepure desired product.

Quantity: 7.02 g (yield: 32%),

Melting point: 121°-122° C.

EXAMPLE 1-a3-ethyl-4-(4'-fluorophenyl)-5-hydroxymethyl-2-methyl-6-(1'-methylethyl]thieno[2,3-b]pyridine(Compound VI-1)

6.83 g (17.7 mmol) of the compound VII-1 was dissolved in dry tolueneunder a nitrogen atmosphere and cooled to 0° C. in an ice bath. To thissolution, 44 ml of a 16 weight % diisobutylaluminium hydride-toluenesolution was dropwise added, and then, the mixture was stirred at 0° C.for 2 hours. After confirming the complete disappearance of the compoundVII-1 by thin layer chromatography, a saturated ammonium chlorideaqueous solution was added thereto at 0° C. to terminate the reaction.Diethyl ether was added to the reaction mixture, and the organic layerwas separated. The gelled substance was dissolved by an addition of asodium hydroxide aqueous solution and newly extracted with ethyl ether.The ethyl ether extracts were put together and dried over anhydrousmagnesium sulfate. The extract was subjected to filtration, and thesolvent was distilled off to obtain the slightly yellow desiredcompound.

Quantity: 5.62 g (Yield: 88%),

Melting point: 188°-191° C.

EXAMPLE 1-b3-ethyl-4-(4'-fluorophenyl)-2-methyl-6-(1'methylethyl)thieno[2,3-b]pyridin-5-yl]carboxyaldehyde(Compound V-1)

5.16 g (23.9 mmol) of pyridinium chlorochromate, 0.92 g of anhydroussodium acetate and 5.48 g (16.0 mmol) of Compound VI-1 were suspended in40 ml of dry dichloromethane. The raction solution was stirred at roomtemperature for 2 hours. Then, the solvent was distilled off underreduced pressure. Diethyl ether was added to the residue, and solublesubstances were extracted. This operation was repeated a few times. Theether layers were put together, and the solvent was distilled off underreduced pressure. The residue was subjected to silica gel columnchromatography (eluent: chloroform) to obtain the white desiredcompound.

Quantity: 4.73 g (yield: 87%),

Melting point: 157°-160° C.

EXAMPLES 1-c and 1-d(E)-3-[3'-ethyl-4'-(4"-fluorophenyl)-2'-methyl-6'-(1"-methylethyl)thieno[2,3-b]pyridin-5'-yl]propenealdehyde(Compound VI-1) EXAMPLE I-c

14.6 g (43.1 mmol) of cis-1-ethoxy-2-(tri-n-butylstannyl)ethylene wasdissolved in 150 ml of dry tetrahydrofuran, and the solution was cooledto -78° C. under a nitrogen atmosphere. 25.4 ml (43.1 mmol) of a 15weight % n-butyl lithium-n-hexane solution was dropwise added to thissolution. The mixture was stirred for 20 minutes, and then, a solutionof 4.60 g (13.5 mmol) of Compound V-1 dissolved in 50.ml of drytetrahydrofuran was dropwise added thereto. The reaction mixture wasstirred at -78° C. for one hour, and then, 10 ml of a saturated ammoniumchloride solution was added thereto to terminate the reaction. Theorganic layer was extracted with diethyl ether. The ether extract waswashed with a saturated sodium chloride aqueous solution and dried overanhydrous magensium sulfate. The solvent was distilled off under reducedpressure, and the residue was subjected to liquid separation betweenn-hexane and acetonitrile. The acetonitrile layer was subjected todistillation under reduced pressure to obtain substantially pureCompound IV- 1.

EXAMPLE 1-d

Compound IV-1 obtained in Example 1-c was dissolved in 70 ml oftetrahydrofuran, and 20 ml of water and 3 g of p-toluenesulfonic acidwere added thereto. The mixture was stirred at room temperature for 2hours. The reaction solution was carefully neutralized with a sodiumhydroxide aqueous solution. Then, diethyl ether was added thereto, andthe extraction was conducted a few times. The extract was washed with asaturated sodium chloride aqueous solution and dried over anhydrousmagnesium sulfate. Then, the solvent was distilled off under reducedpressure. The residue was subjected to silica gel column chromatography(eluent: ethyl acetate/n-hexane=1/9 (v/v)) to obtain the desiredcompound as yellow substance.

Quantity: 3.83 g (yield: 77%)

Melting point: 111°-112° C.

EXAMPLE 1-e Ethyl(E)-7-[3'-ethyl-4'-(4"-fluorophenyl-2'-methyl-6'-(1"-methylethyl)thieno[2,3-b]pyridin-5'-yl]-5-hydroxy-3-oxohept-6-enoate(Compound II-1)

1 67 g of 60% sodium hydride was washed with n-hexane, dried under anitrogen stream and then suspended in 200 ml of dry tetrahydrofuran. Thesuspension was cooled to 0° C. under a nitrogen atmosphere, and 5.13 ml(40.3 mmol) of ethyl acetoacetate was dropwise added thereto. Themixture was stirred for 15 minutes. Then, 25.3 ml (40.3 mmol) of a 15weight % (n-butyl lithium-n-hexane solution was dropwise added thereto,and the mixture was stirred for 30 minutes. Further, a solution of 3.70g (10.1 mmol) of Compound III-1 dissolved in dry tetrahydrofuran wasdropwise added thereto, and the mixture was stirred for 15 minutes. 10ml of a saturated ammonium chloride aqueous solution was added to thereaction mixture at 0° C., and the mixture was extracted three timeswith diethyl ether. The ether solution was washed with a saturatedsodium chloride aqueous solution, dried over anhydrous magnesium sulfateand then evaporated under reduced pressure to dryness. The residue wassubjected to silica gel column chromatrography (eluent: chloroform) toobtain the slightly yellow desired compound.

Quantity 5.00 g (yield: 99%), Melting point: 85°-88° C.

EXAMPLE 1-f Ethyl(E)-7-[3'-ethyl-4'-(4"-fluorophenyl)-2'-methyl-6'-(1"-methylethyl)thieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoate(Compound I-1-1)

3.06 g (6.15 mmol) of Compound II-1 was dissolved in 40 ml of ethanolunder a nitrogen atmosphere, and the mixture was cooled to 0° C. Then,700 mg (18.5 mmol) of sodium borohydride was added thereto, and themixture was stirred for one hour. The mixture was carefully neutralizedby an addition of a 10% hydrochloric acid aqueous solution and thenextracted three times with diethyl ether. The diethyl ether solution waswashed with a saturated sodium chloride aqueous solution, dried overanhydrous magnesium sulfate and then evaporated under reduced pressureto dryness. The residual oil was purified by silica gel columnchromatography (eluent: ethanol/chloroform=3/97 (v/v) to obtain thewhite desired product.

Quantity: 2.62 g (yield: 85%),

Melting point: 101°-105° C.

EXAMPLE 2 Sodium(E)-7-[3'-ethyl-4'-(4"-fluorophenyl)-2'-methyl-6'-(1"-methylethyl)thieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoate(Compound I-5-1)

600 mg (1.20 mmol) of Compound I-1-1 was dissolved in 5 ml of ethanol,and 2.40 ml of a 0.5N sodium hydroxide aqueous solution was dropwiseadded thereto. The mixture was stirred at room temperature for 15minutes. Then, ethanol was distilled off under reduced pressure, 7 ml ofwater was added thereto and extracted with diethyl ether. The aqueouslayer was freeze-dried to obtain hygroscopic white powder.

Quantity: 570 mg (yield: 96%),

Melting point: 263°-267° C.

In the same manner as in Example 1-a₀, Compounds VII-2 to VII-11 wereprepared. Physical properties of the compounds thereby obtained wereshown in the following Table.

                  TABLE 2                                                         ______________________________________                                         ##STR35##                                                                                                              Melting                             Compound                                                                              R.sup.1                                                                              R.sup.2 R.sup.3                                                                            R.sup.4                                                                           R.sup.5                                                                            R.sup.21                                                                           point (°C.)                  ______________________________________                                        VII-2   H      Me      4-F  H   i-Pr Et   97-98                               VII-3   H      Ph      4-F  H   i-Pr Et   109-101                             VII-4   Ph     Me      4-F  H   i-Pr Et   137-138                             VII-5   H      i-Pr    4-F  H   i-Pr Et   63-65                               VII-6   (CH.sub.2).sub.4                                                                         4-F    H   i-Pr Et   126-127                               VII-7   Et     Me      4-F  H   c-Pr Me   168-169                             VII-8   (CH.sub.2).sub.3                                                                         4-F    H   i-Pr Et   142-144                               VII-9   (CH.sub.2).sub. 3                                                                        4-F    H   c-Pr Me   168-170                                VII-10 (CH.sub.2).sub.5                                                                         4-F    H   c-Pr Me   --                                     VII-11 H      H       4-F  H   c-Pr Me   137-138                             ______________________________________                                    

H-NMR of Compound VII-10 (CDCl₃) δ ppm: 0.9-1.4(m,6H), 1.5-2.1(m,6H),2.7-3.3(m,3H), 3.48(s,3H), 6.9-7.2(m,4H).

In the same manner as in Example 1-a, Compounds VI-2 to VI-11 wereprepared. Physical properties of the compounds thereby obtained areshown in the following Table.

                  TABLE 3                                                         ______________________________________                                         ##STR36##                                                                                                            Melting                               Compound R.sup.1                                                                              R.sup.2  R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            point (°C.)                    ______________________________________                                        VI-2     H      Me       4-F  H    i-Pr 157-158                               VI-3     H      Ph       4-F  H    i-Pr 105-208                               VI-4     Ph     Me       4-F  H    i-Pr 211-212                               VI-5     H      i-Pr     4-F  H    i-Pr 149-152                               VI-6     (CH.sub.2).sub.4                                                                          4-F    H    i-Pr 145-147                                 VI-7     Et     Me       4-F  H    c-Pr 118-120                               VI-8     (CH.sub.2).sub.3                                                                          4-F    H    i-Pr 118-120                                 VI-9     (CH.sub.2).sub.3                                                                          4-F    H    c-Pr --                                       VI-10   (CH.sub.2).sub.5                                                                          4-F    H    c-Pr 169-170                                  VI-11   H      H        4-F  H    c-Pr 133-135                               ______________________________________                                    

H-NM of Compound VI-9 (CDCl₃) δ ppm: 0.9-1.3(m,4H), 1.7-1.9(m,1H),2.0-2.6(m,5H), 2.7-3.1(m,2H), 4.59(bs,2H), 6.9-7.2(m,4H).

In the same manner as in Example 1-b, Compounds V-2 were V-11 wereprepared. Physical properties of the compounds thereby obtained areshown in the following Table.

                  TABLE 4                                                         ______________________________________                                         ##STR37##                                                                                                            Melting                               Compound R.sup.1                                                                              R.sup.2  R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            point (°C.)                    ______________________________________                                        V-2      H      Me       4-F  H    i-Pr 147-148                               V-3      H      Ph       4-F  H    i-Pr 158-160                               V-4      Ph     Me       4-F  H    i-Pr 172.5-173                             V-5      H      i-Pr     4-F  H    i-Pr 140-143                               V-6      (CH.sub.2).sub.4                                                                          4-F    H    i-Pr 181-182                                 V-7      Et     Me       4-F  H    c-Pr 174-176                               V-8      (CH.sub.2).sub.3                                                                          4-F    H    i-Pr 138-139                                 V-9      (CH.sub.2).sub.3                                                                          4-F    H    c-Pr 145-146                                  V-10    (CH.sub.2).sub.5                                                                          4-F    H    c-Pr 176-178                                  V-11    H      H        4-F  H    c-Pr 133-135                               ______________________________________                                    

In the same manner as in Examples 1-c and 1-d, Compounds III-2 to III-11were prepared. Physical properties of the compounds thereby obtained areshown in the following Table.

                  TABLE 5                                                         ______________________________________                                         ##STR38##                                                                                                            Melting                               compound R.sup.1                                                                              R.sup.2  R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            point (°C.)                    ______________________________________                                        III-2    H      Me       4-F  H    i-Pr Oil                                   III-3    H      Ph       4-F  H    i-Pr 197-200                               III-4    Ph     Me       4-F  H    i-Pr 166-167                               III-5    H      i-Pr     4-F  H    i-Pr 130-133                               III-6    (CH.sub.2).sub.4                                                                          4-F    H    i-Pr 170-172                                 III-7    Et     Me       4-F  H    c-Pr 136-138                               III-8    (CH.sub.2).sub.3                                                                          4-F    H    i-Pr 139-143                                 III-9    (CH.sub.2).sub.3                                                                          4-F    H    c-Pr 172-175                                  III-10  (CH.sub.2).sub. 5                                                                         4-F    H    c-Pr 167-169                                  III-11  H      H        4-F  H    c-Pr 125-127                               ______________________________________                                    

H NMR of Compound III-2 (CDCl₃) δ ppm: 1.33(d,J=7Hz,6H),2.48(d,J=1Hz,3H), 3.38(Heptalet, J=7Hz,1H), 5.87(dd,J=16Hz,J=8Hz,1H),6.4(d,J=1Hz,1H), 7.0-7.6(m,4H),7.43 (d, J=16Hz, 1H), 9.31(d,J=8Hz,1H).

In the same manner as in Example 1-e, Compounds II-2 to II-11 wereprepared. Physical properties of the compounds thereby obtained areshown in the following Table.

                  TABLE 6                                                         ______________________________________                                         ##STR39##                                                                                                               Melting                            Compound                                                                              R.sup.1                                                                              R.sup.2 R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            R.sup.12                                                                           point (°C.)                 ______________________________________                                        II-2    H      Me      4-F  H    i-Pr Et   102-106                            II-3    H      Ph      4-F  H    i-Pr Et   115-117                            II-4    Ph     Me      4-F  H    i-Pr Et   109-111                            II-5    H      i-Pr    4-F  H    i-Pr Et   82-85                              II-6    (CH.sub.2).sub.4                                                                         4-F    H    i-Pr Et   104-107                              II-7    Et     Me      4-F  H    c-Pr Et   --                                 II-8    (CH.sub.2).sub.3                                                                         4-F    H    i-Pr Et   106-108                              II-9    (CH.sub.2).sub.3                                                                         4-F    H    c-Pr Et   --                                    II-10  (CH.sub.2).sub.5                                                                         4-F    H    c-Pr Et   --                                    II-11  H      H       4-F  H    c-Pr Et   --                                 ______________________________________                                    

H-NMR of Compound II-7 (CDCl₃) δ ppm: 0.62(t,J=7Hz,3H), 0.8-1.4(m,4H),1.24(t,J=7Hz, 3H), 1.9-2.5(m,3H), 2.52(s,3H), 2.66(d,J=7Hz, 2H),2.8-3.0(m,1H), 3.55(s,2H), 4.32(q,J=7Hz, 2H), 4.5-4.8(m,1H),5.64(dd,J=16Hz,J=6Hz,1H), 6.49(dd,J=16Hz,J=1Hz,1H), 7.1-7.4(m,4H)

H-NMR of Compound II-9 (CDCl₃) δ ppm: 0.8-1.4(m,4H), 1.25(t,J=7Hz,3H),1.9-2.3(m,6H), 2.49(d,J=6Hz,2H), 2.6-3.1(m,2H), 3.36(s,2H),4.13(q,J=7Hz,2H), 4.3-4.7(m,1H), 5.48(dd,J=16Hz,J=6Hz,1H),6.48(dd,J=16Hz,J=1Hz,1H), 6.9-7.2(m,4H)

H-NMR of Compound II-10 (CDCl₃) δppm: 0.8-1.4(m,6H), 1.25(t,J=7Hz,3H),1.5-2.1(m,7H), 2.1-2.4(m,1H), 2.48(d,J=6Hz,2H), 2.6-2.9(m, 2H),3.35(s,2H), 4.11(q,J=7Hz,2H), 4.3-4.7(m,1H), 5.43(dd,J=16Hz,J=6H),6.31(dd,J=16Hz,J=1Hz,1H), 6.9-7.2(m,4H)

H-NMR of Compound II-11 (CDCl₃) δ ppm: 0.8-1.4(m,4H), 1.24(t,J=7Hz,3H),2.0-2.4(m,1H), 2.51(d,J=6Hz,2H), 2.7-3.1(m,1H), 3.36(s,2H),4.12(q,J=7Hz, 2H), 4.3-4.7(m,1H), 5.43(dd,J=16Hz,J=6Hz,1H),6.57(dd,J=16Hz,J=1Hz,1H), 6.69(d,J=6Hz,1H), 6.9-7.2(m,5H)

In the same manner as in Example 1-f, Compounds I-1-2 to I-1-11 wereprepared. Physical properties of the compounds thereby obtained areshown in the following Table.

                  TABLE 7                                                         ______________________________________                                         ##STR40##                                                                                                               Melting                            Compound                                                                              R.sup.1                                                                              R.sup.2 R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            R.sup.12                                                                           point (°C.)                 ______________________________________                                        I-1-2   H      Me      4-F  H    i-Pr Et   Oil                                I-1-3   H      Ph      4-F  H    i-Pr Et   115-119                            I-1-4   Ph     Me      4-F  H    i-Pr Et   81-86                              I-1-5   H      i-Pr    4-F  H    i-Pr Et   88-91                              I-1-6   (CH.sub.2).sub.4                                                                         4-F    H    i-Pr Et   124-127                              I-1-7   Et     Me      4-F  H    c-Pr Et   105-108                            I-1-8   (CH.sub.2).sub.3                                                                         4-F     H   i-Pr Et   130-133                              I-1-9   (CH.sub.2).sub.3                                                                         4-F    H    c-Pr Et   --                                    I-1-10 (CH.sub.2).sub.5                                                                         4-F    H    c-Pr Et   --                                    I-1-11 H      H       4-F  H    c-Pr Et   --                                 ______________________________________                                    

H-NMR of Compound I-1-2 (CDCl₃) δ ppm: 1.29(t,J=7Hz,3H),1.31(d,J=7Hz,6H), 1.4-1.9 (m,2H), 2.3-2.6(m,2H), 2.50(d,J=1Hz,3H),3.1-3.8(m,3H), 3.8-4.6(m,2H), 4.19(q,J=7Hz, 2H), 5.1-5.5(m,1H),6.49(d,J=1Hz,1H), 6.6-7.3(m,5H)

H-NMR of Compound I-1-9 (CDCl₃) δ ppm: 0.8-1.7(m8H), 1.29(t,J=7Hz,3H),1.9-2.5(m,6H), 2.8-3.1(m,2H), 3.4-3.7(m,1H), 3.8-4.5(m,2H),4.18(q,J=7Hz,2H), 5.4-5.8(m,1H), 6.9-6.7(m, 1H), 7.0-7.3(m,4H)

H-NMR of Compound I-1-10 (CDCl₃) δ ppm: 0.8-1.4(m,6H), 1.28(t,J=7Hz,3H),1.5-1.8(m,4H), 1.8-2.1(m,3H), 2.2-2.6(m,4H), 2.7-3.1(m,3H),3.5-3.7(m,1H), 4.0-4.4(m,2H), 4.18(q,J=7Hz, 2H), 5.4-57.(m,1H),6.3-6.6(m,1H), 7.0-7.3 (m,4H)

H-NMR of Compound I-1-11 (CDCl₃) δ ppm: 0.8-1.5(m,5H), 1.28(t,J=7Hz,3H),1.6-2.0(m,1H), 2.1-2.6(m,4H), 3.6-3.9(m,1H), 4.0-4.7(m,4H),5.3-5.7(m,1H), 6.5-6.9(m,2H), 7.0-7.4(m,5H)

In the same manner as in Example 2, Compounds I-5-2 to I-5-11 wereprepared. Physical properties of the compounds thereby obtained areshown in the following Table.

                  TABLE 8                                                         ______________________________________                                         ##STR41##                                                                    Com-                                     Melting                              pound  R.sup.1                                                                              R.sup.2 R.sup.3                                                                            R.sup.4                                                                           R.sup.5                                                                            R.sup.12                                                                           point (°C.)                   ______________________________________                                        I-5-2  H      Me      4-F  H   i-Pr Na   228-235                                                                       (Decomposed)                         I-5-3  H      Ph      4-F  H   i-Pr Na   209-214                                                                       (Decomposed)                         I-5-4  Ph     Me      4-F  H   i-Pr Na   286-289                                                                       (Decomposed)                         I-5-5  H      i-Pr    4-F  H   i-Pr Na   218-223                                                                       (Decomposed)                         I-5-6  (CH.sub.2).sub.4                                                                         4-F    H   i-Pr  Na  222-227                                                                       (Decomposed)                           I-5-7  Et     Me      4-F  H   c-Pr Na   212-216                                                                       (Decomposed)                         I-5-8  (CH.sub.2).sub.3                                                                         4-F    H   i-Pr Na   209-213                                                                       (Decomposed)                           I-5-9  (CH.sub.2).sub.3                                                                         4-F    H   c-Pr Na   210-217                                                                       (Decomposed)                            I-5-10                                                                              (CH.sub.2).sub.5                                                                         4-F    H   c-Pr Na   242-248                                                                       (Decomposed)                            I-5-11                                                                              H      H       4-F  H   c-Pr Na   249-253                              ______________________________________                                    

EXAMPLE 3(E)-trans-6-[2'-(6"-cyclopropyl-4"-(4"'-fluorophenyl)-thieno[2,3-b]pyridin-5"-yl)ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(Compound I-3-11)

Compound I-1-11 was hydrolyzed in ethanol with a diluted sodiumhydroxide aqueous solution to form the corresponding carbaxylic acid(Compound I-2-11). Further, the carboxylic acid was azeotropicallydehydrated in toluene or dehydrated at room temperature indichloromethane by using N-cyclohexyl-N'-(2'-methylmorpholinoethyl)carbodiimide p-toluenesulfonate, to obtain the desired lactone (CompoundI-3-11). The crude lactone was purified by recrystallization from ethylacetate to obtain the pure translactone.

Melting point: 203°-205° C.

FORMULATION EXAMPLE 1

    ______________________________________                                        Tablets                                                                       ______________________________________                                        Compound I-5-6      1.0 g                                                     Lactose             5.0 g                                                     Crystal cellulose powder                                                                          8.0 g                                                     Corn starch         3.0 g                                                     Hydroxypropyl cellulose                                                                           1.0 g                                                     CMC-Ca              1.5 g                                                     Magnesium stearate  0.5 g                                                     Total               20.0 g                                                    ______________________________________                                    

The above components were mixed by a usual method and then tabletted toproduce 100 sugar coating tablets each containing 10 mg of the activeingredient.

FORMULATION EXAMPLE 2

    ______________________________________                                        Capsules                                                                      ______________________________________                                        Compound I-5-6      1.0 g                                                     Lactose             3.5 g                                                     Crystal cellulose powder                                                                          10.0 g                                                    Magnesium stearate  0.5 g                                                     Total               15.0 g                                                    ______________________________________                                    

The above components were mixed by a usual method and then packed in No.4 gelatin capsules to obtain 100 capsules each containing 10 mg of theactive ingredient.

FORMULATION EXAMPLE 3

    ______________________________________                                        Soft capsules                                                                 ______________________________________                                        Compound I-5-6       1.00 g                                                   PEG (polyethylene glycol) 400                                                                      3.89 g                                                   Saturated fatty acid triglyceride                                                                  15.00 g                                                  Peppermint oil       0.01 g                                                   Polysorbate 80       0.10 g                                                   Total                20.00 g                                                  ______________________________________                                    

The above components were mixed and packed in No. 3 soft gelatincapsules by a usual method to obtain 100 soft capsules each containing10 mg of the active ingredient.

FORMULATION EXAMPLE 4

    ______________________________________                                        Ointment                                                                      ______________________________________                                        Compound I-5-6       1.0 g (10.0 g)                                           Liquid Paraffin      10.0 g (10.0 g)                                          Cetanol              20.0 g (20.0 g)                                          White vaseline       68.4 g (59.4 g)                                          Ethylparaben         0.1 g ( 0.1 g)                                           l-menthol            0.5 g ( 0.5 g)                                           Total               100.0 g                                                   ______________________________________                                    

The above components were mixed by a usual method to obtain a 1% (10%)ointment.

FORMULATION EXAMPLE 5

    ______________________________________                                        Suppository                                                                   ______________________________________                                        Compound I-5-6  1.0 g                                                         Witepsol H15*   46.9 g                                                        Witepsol W35*   52.0 g                                                        Polysorbate 80  0.1 g                                                         Total           100.0 g                                                       ______________________________________                                         *Trademark for triglyceride compound                                     

The above components were melt-mixed by a usual method and poured intosupository containers, followed by cooling for solidification to obtain100 suppositories of 1 g each containing 10 mg of the active ingredient.

FORMULATION EXAMPLE 6

    ______________________________________                                        Injection formulation                                                         ______________________________________                                        Compound I-5-6          1 mg                                                  Distilled water for     5 ml                                                  injection formulation                                                         ______________________________________                                    

The formulation is prepared by dissolving the compound in the distilledwater whenever it is required.

FORMULATION EXAMPLE 7

    ______________________________________                                        Granules                                                                      ______________________________________                                        Compound I-5-6      1.0 g                                                     Lactose             6.0 g                                                     Crystal cellulose powder                                                                          6.5 g                                                     Corn starch         5.0 g                                                     Hydroxypropyl cellulose                                                                           1.0 g                                                     Magnesium stearate  0.5 g                                                     Total               20.0 g                                                    ______________________________________                                    

The above components were granulated by a usual method and packaged toobtain 100 packages each containing 200 mg of the granules so that eachpackage contains 10 mg of the active ingredient.

We claim:
 1. A compound of the formula ##STR42## wherein R¹ and R² areindependently hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, C₁₋₆alkoxy, fluoro, chloro, bromo, ##STR43## (wherein R⁶, R⁷ and R⁸ areindependently hydrogen, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₃₋₇ cycloalkyl,trifluoromethyl, fluoro, chloro or bromo), 2-, 3- or 4-pyridyl, 2- or5-pyrimidyl, 2- or 3-thienyl, 2- or 3-furyl, ##STR44## wherein R₆ is asdefined above), --NR⁹ R¹⁰ (wherein R⁹ and R¹⁰ are independentlyhydrogen, C₁₋₄ alkyl, ##STR45## (wherein R⁶ is as defined above, and mis 1, 2 or 3), or ⁹ and R¹⁰ together form --(CH₂)_(j) -- (wherein j is3, 4 or 5)); or C₁₋₃ alkyl substituted by ##STR46## (wherein R⁶ is asdefined above) and by 0, 1 or 2 members selected from the groupconsisting of C₁₋₈ alkyl or α- or β-naphthyl; or R¹ and R² together formC₂₋₆ alkylene unsubstituted or substituted by 1 to 3 members selectedfrom the group consisting of C₁₋₄ alkyl, C₃₋₇ cycloalkyl, fluoro, chloroand bromo, and by one member selected from the group consisting of##STR47## (wherein R⁶ is as defined above), or --(CHR²³)_(k)--A--(CHR²⁴)_(l) -- (wherein k and l are respectively 0, 1, 2 or 3, andA is --C(R¹⁸)═C(R¹⁹)-- (wherein R¹⁸ and R¹⁹ are independently hydrogenor C₁₋₃ alkyl), --O--, --S-- or --N(R²⁰)-- (wherein R²⁰ is hydrogen,C₁₋₄ alkyl or ##STR48## (wherein R⁶ is as defined above, and m is 1, 2or 3)), and R²³ and R²⁴ are independently hydrogen or C₁₋₄ alkyl), or--CH═CH--CH═CH--; R³ and R⁴ are independently hydrogen, C₁₋₈ alkyl, C₃₋₇cycloalkyl, C₁₋₃ alkoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, R²⁵R²⁶ N-- (wherein R²⁵ and R²⁶ are independently hydrogen or C₁₋₃ alkyl),trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro,bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy,diphenyl-t-butylsilyloxy, hydroxymethyl or --O(CH₂)_(l) OR¹⁵ (whereinR¹⁵ is hydrogen or C₁₋₃ alkyl, and l is 1, 2 or 3); or when locatedortho position to each other, R³ and R⁴ may together form--CH═CH--CH═CH-- or methylenedioxy; Y is --CH₂ --, --CH₂ CH₂ --,--CH═CH--, --CH₂ --CH═CH--, --CH═CH--CH₂ --, --C(CH₃)═CH-- or--CH═C(CH₃)--; Z is --Q--CH₂ WCH₂ --CO₂ R¹², ##STR49## (wherein Q is--C(O)--, --C(OR¹³)₂ -- or --CH(OH)--: W is --C(O)--, --C(OR¹³)₂ -- or--C(R¹¹)(OH)--; R¹¹ is hydrogen or C₁₋₃ alkyl; R¹² is hydrogen or R¹⁴(wherein R¹⁴ is alkyl moiety of chemically or physiologicallyhydrolyzable alkyl ester or M (wherein M is NHR²⁷ R²⁸ R²⁹ (wherein R²⁷,R²⁸ and R²⁹ are independently hydrogen or C₁₋₄ alkyl), sodium potassiumor 1/2 calcium); two R¹³ are independently primary or secondary C₁₋₆alkyl; or two R¹³ together form --(CH₂)₂ -- or --(CH₂)₃ --; R¹⁶ and R¹⁷are independently hydrogen or C₁₋₃ alkyl; or R¹⁶ and R¹⁷ together form--(CH₂)₂ -- or --(CH₂)₃ --; and R⁵ is hydrogen, C₁₋₈ alkyl, C₂₋₆alkenyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, or ##STR50## (wherein R⁶ isas defined above), or C₁₋₃ alkyl substituted by one member selected fromthe group consisting of ##STR51## (wherein R⁶, R⁷ and R⁸ are as definedabove) and by 0, 1 or 2 members selected from the group consisting ofC₁₋₃ alkyl.
 2. The compound according to claim 1, wherein in the formulaI, R¹ and R² are independently hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇cycloalkyl, fluoro, chloro, bromo, ##STR52## (wherein R⁶, R⁷ and R⁸ areindependently hydrogen, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₃₋₇ cycloalkyl,trifluoromethyl, fluoro, chloro or bromo), 2-, 3- or 4-pyridyl, 2- or3-thienyl, 2- or 3-furyl; C₁₋₃ alkyl substituted by ##STR53## (whereinR⁶ is as defined above) and by 0, 1 or 2 members selected from the groupconsisting of C₁₋₈ alkyl or α- or β-naphthyl; or R¹ and R² together formC₂₋₆ alkylene unsubstituted or substituted by 1 to 3 members selectedfrom the group consisting of C₁₋₄ alkyl, C₃₋₇ cycloalkyl, fluoro, chloroand bromo and by one member selected from the group consisting of##STR54## (wherein R⁶ is as defined above) or --(CHR²³)_(k)--A--(CHR²⁴)_(l) -- (wherein k and l are independently 0, 1, 2 or 3, Ais --C(R¹⁸)═C(R¹⁹)-- (wherein R¹⁸ and R¹⁹ are independently hydrogen orC₁₋₃ alkyl), --O--, --S-- or --N(R²⁰)-- (wherein R²⁰ is hydrogen, C₁₋₄alkyl or ##STR55## (wherein R⁶ is as defined above, and m is 1, 2 or3)), and R²³ and R²⁴ are independently hydrogen or C₁₋₄ alkyl); R³ andR⁴ are independently hydrogen, C₁₋₈ alkyl, C₁₋₃ alkoxy, n-butoxy,i-butoxy, sec-butoxy, t-butoxy, trifluoromethyl, fluoro, chloro, bromo,phenoxy, benzyloxy, hydroxy, trimethylsilyloxy,diphenyl-t-butylsilyloxy, hydroxymethyl or --O(CH₂)_(l) OR¹⁵ (whereinR¹⁵ is hydrogen or C₁₋₃ alkyl, and l is 1, 2 or 3); or when located atthe ortho pOsition to each other, R³ and R⁴ may together form methylenedioxy; Y is --CH₂ CH₂ -- or --CH═CH--; Z is --Q--CH₂ WCH₂ --CO₂ R¹²,##STR56## (wherein Q is --C(O)-- or --CH(OH)--; W is --C(O)-- or--CH(OH)--; R¹² is defined in claim 1); and R₅ is C₁₋₈ alkyl, C₂₋₆alkenyl or C₃₋₇ cycloalkyl.
 3. The compound according to claim 1,wherein in the formula I, R¹ and R² are independently hydrogen, C₁₋₈alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, ##STR57## (wherein R⁶, R⁷ and R⁸are independently hydrogen, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₃₋₇ cycloalkyl,trifluoromethyl, fluoro, chloro or bromo) or α- or β-naphthyl; or R¹ andR² together form C₂₋₆ alkylene unsubstituted or substituted by 1 to 3members selected from the group consisting of C₁₋₄ alkyl, C₃₋₇cycloalkyl, fluoro, chloro and bromo, and by one member selected fromthe group consisting of ##STR58## (wherein R⁶ is as defined above); R³and R⁴ are as defined in claim 2 and located at the 3- and 4-position;--CH₂ CH₂ -- or (E)--CH═CH--; Z is as defined in claim 2; and R⁵ isprimary or secondary C₁₋₄ alkyl or C₃₋₆ cycloalkyl.
 4. The compoundaccording to claim 1, wherein in the formula I, R¹ and R² areindependently hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl or##STR59## (wherein R⁶, R⁷ and R⁸ are as defined in claim 3); or R¹ andR² together form C₂₋₆ alkylene unsubstituted or substituted by 1 to 3members selected from the group consisiting of C₁₋₄ alkyl, C₃₋₇cycloalkyl, fluoro, chloro and bromo, and by one member selected fromthe group consisting of ##STR60## (wherein R⁶ is as defined above); R³and R⁴ are independently hydrogen, C₁₋₈ alkyl, fluoro, chloro or bromo,and they are located-at the 3- and 4-position; Y and Z are as defined inclaim 3; and R⁵ is ethyl, n-propyl, i-propyl or cyclopropyl.
 5. Thecompound according to claim 1, wherein in the formula I, R¹ and R² areindependently hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl,ibutyl, sec-butyl, t-butyl, n-pentyl, 1,2-dimethylpentyl, n-hexyl,n-heptyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,4-methylcyclohexyl, cycloheptyl, cyclopropylmethyl, vinyl,1-methylvinyl, 1-propenyl, allyl, 1-methyl-1-propenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-butenyl, 1-ethylvinyl,1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl,1-ethyl-2-propenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl,2-methyl-1-butenyl, 1-i-propylvinyl, 1-methyl-1-pentyl or phenyl; or R¹and R² together form ethylene, trimethylene, tetramethylene,pentamethylene, methyltetramethylene, chlorotetramethylene, orphenyltetramethylene; when R⁴ is hydrogen, R³ is hydrogen, 3-methyl,4-methyl, 3-chloro, 4-chloro, 3-fluoro or 4-fluoro; or R³ and R⁴together form 3-methyl-4-chloro, 3,5-dichloro, 3,5-difluoro,3,5-dimethyl or 3-methyl-4-fluoro; Y and Z are as defined in claim 3;and R.sub. 5 is i-propyl or cyclopropyl.
 6. The compound according toclaim 1, wherein in the formula I, R¹, R², R³, R⁴, Y and Z are asdefined in claim 1; and R⁵ is cyclopropyl.
 7. The compound according toclaim 1, which is(E)-7-[3'-ethyl-4'-(4"-fluorophenyl)-2'-methyl-6'-(1"-methylethyl)thieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position. 8.The compound according to claim 1, which is(E)-7-[4'-(4"-fluorophenyl)-2'-methyl-6'-(1"-methylethyl)thieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position. 9.The compound according to claim 1, which is(E)-7-[4'-(4"-fluorophenyl)-6'-(1"-methylethyl)-2'-phenylthieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position. 10.The compound according to claim 1, which is(E)-7-[4'-(4"-fluorophenyl)-2'-methyl-6'-(1"-methylethyl)-3'-phenylthieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position. 11.The compound according to claim 1, which is(E)-7-[4'-(4"-fluorophenyl)-2'-isopropyl-6-(1"-methylethyl)thieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position. 12.The compound according to claim 1, which is (E)-7-[4'-(4"-fluorophenyl)-6'-(1"-methylethyl)-2',3'-tetramethylenethieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position. 13.The compound according to claim 1, which is(E)-7-[6'-cyclopropyl-3'-ethyl-4'-(4"-fluorophenyl)-2'methylthieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position. 14.The compound according to claim 1, which is(E)-7-[4'-(4"-fluorophenyl)-6'-(1"-methylethyl)-2',3'-trimethylenethieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position. 15.The compound according to claim 1, which is(E)-7-[6'-cyclopropyl-4'-(4"-fluorophenyl)-2', 3'-trimethylenetrieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoic acid, a sodium salt,methyl ester, ethyl ester, n-propyl ester or i propyl ester of thecarboxylic acid, or a lactone formed by the condensation of thecarboxylic acid with hydroxy at the 5-position.
 16. The compoundaccording to claim 1, which is(E)-7[6'-cyclopropyl-4'-(4"-fluorophenyl)-2',3'-pentamethylenethieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position. 17.The compound according to claim 1, which is(E)-7[6'-cyclopropyl-4'-(4"-fluorophenyl)thieno[2,3-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position. 18.An anti-hyperlipidemia agent comprising the compound of formula I asdefined in claim
 1. 19. An anti-hyperlipoproteinemia agent comprisingthe compound of the formula I as defined in claim
 1. 20. Ananti-atherosclerosis agent comprising the compound of formula I asdefined in claim
 1. 21. A method for reducing hyperlipidemia,hyperlipoproteinemia or atherosclerosis, which comprises administeringan effective amount of the compound of the formula I as defined in claim1.